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PHYSIOLOGICAL REVIEWS Vol. 78 No. 1 January 1998, pp. 1-33
Copyright ©1998 by the American Physiological Society
Pediatric Surgical Research Laboratories, Massachusetts General Hospital, and Department of Genetics and Surgery, Harvard Medical School, Boston, Massachusetts
I. INTRODUCTION
II. SEX-DETERMINING ROLE OF HUMAN Y CHROMOSOME
III. IDENTIFICATION OF THE SEX-DETERMINING GENE SRY
IV. MUTATIONS IN SRY EXPLAIN A SUBSET OF PATIENTS WITH 46, XY PURE GONADAL DYSGENESIS
V. TRANSLOCATION OF SRY TO THE X CHROMOSOME OR AUTOSOMES EXPLAINS A SUBSET OF PATIENTS WITH 46, XX TRUE HERMAPHRODITISM
VI. BIOCHEMICAL ACTIVITIES OF SRY: HOW DOES SRY DETERMINE SEX?
A. SOX Genes and Functions
B. Factors Involved in MIS Regulation
C. Mutated SRY From Sex-Reversed Patients Fails to Activate MIS
D. Superactivator SRY Isoleucine 68 Phenylalanine
E. Functional Mapping of the MIS Promoter Response to SRY
F. Additional Factors Involved in Regulation of the MIS Promoter
VII. SRY TRANSCRIPTION UNIT: WHAT REGULATES SRY EXPRESSION?
VIII. AUTOSOMAL AND X-LINKED GENES INVOLVED IN SEX DETERMINATION AND DIFFERENTIATION
A. MIS and Sex Differentiation
B. Mutation of the MIS Type II Receptor and MIS Receptor Signal Transduction
C. Role of Androgens and Sex Steroids in Sex Differentiation
D. Defects in Steroid Biosynthesis Lead to an Intersex Phenotype and Congenital Adrenal Hyperplasia
E. Defects in the Androgen Receptor Lead to Testicular Feminization
F. Defects in Steroid 5-Reductase Result in an Intersex Phenotype
G. Additional Autosomal Genes Involved in Sex Differentiation
IX. TISSUE-SPECIFIC MARKERS OF TESTICULAR DIFFERENTIATION
X. CONCLUSIONS
REFERENCES
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 Top References
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Haqq, Christopher M., and Patricia K. Donahoe. Regulation of Sexual Dimorphism in Mammals. Physiol. Rev. 78: 1-33, 1998. 
Sexual dimorphism in humans has been the subject of wonder for centuries. In 355 BC, Aristotle postulated that sexual dimorphism arose from differences in the heat of semen at the time of copulation. In his scheme, hot semen generated males, whereas cold semen made females (Jacquart, D., and C. Thomasset. Sexuality and Medicine in the Middle Ages, 1988). In medieval times, there was great controversy about the existence of a female pope, who may have in fact had an intersex phenotype (New, M. I., and E. S. Kitzinger. J. Clin. Endocrinol. Metab. 76: 3-13, 1993.). Recent years have seen a resurgence of interest in mechanisms controlling sexual differentiation in mammals. Sex differentiation relies on establishment of chromosomal sex at fertilization, followed by the differentiation of gonads, and ultimately the establishment of phenotypic sex in its final form at puberty. Each event in sex determination depends on the preceding event, and normally, chromosomal, gonadal, and somatic sex all agree. There are, however, instances where chromosomal, gonadal, or somatic sex do not agree, and sexual differentiation is ambiguous, with male and female characteristics combined in a single individual. In humans, well-characterized patients are 46, XY women who have the syndrome of pure gonadal dysgenesis, and a subset of true hermaphrodites are phenotypic men with a 46, XX karyotype. Analysis of such individuals has permitted identification of some of the molecules involved in sex determination, including SRY (sex-determining region Y gene), which is a Y chromosomal gene fulfilling the genetic and conceptual requirements of a testis-determining factor. The purpose of this review is to summarize the molecular basis for syndromes of sexual ambiguity seen in human patients and to identify areas where further research is needed. Understanding how sex-specific gene activity is orchestrated may provide insight into the molecular basis of other cell fate decisions during development which, in turn, may lead to an understanding of aberrant cell fate decisions made in patients with birth defects and during neoplastic change.
Fetal sexual differentiation relies on translation of chromosomal sex established at fertilization into gonadal sex and somatic sex as development proceeds. In cases where chromosomal, gonadal, and somatic sex are incongruent in human infants and children, rapid establishment of the diagnosis and implementation of medical and surgical management is of paramount importance (reviewed by Refs. 97 and 115), since gender identity is so important to psychological well-being throughout life. In this review, we briefly discuss the history of research on sex determination, since this has been the topic of recent reviews (e.g., Refs. 47, 148, 159), and then focus on more recent developments in the field. Rather than being comprehensive, we have highlighted work that may define molecules important in the processes of sex determination and sex differentiation. Chromsomal determination of sex was discovered and influenced by work in Drosophila melanogaster at the turn of the century. T. H. Morgan showed that XX fruit flies develop as females, whereas XY flies develop as males. These studies showed that the critical signal for sex determination in flies was the ratio of X chromosomes to autosomes, since XX flies are female and XO flies are sterile males. This was adopted as a model for sex determination in mammals in the 1920s when T. S. Painter showed that female mammals have XX constitution whereas males have X and Y chromosomes (319). This early model was overturned in the late 1950s when it was found that the human Y chromosome specifies development of the testis (reviewed in Ref. 279). With the development of specific staining techniques for chromosomes, Ford et al. (121) and Jacobs and Strong (207) were able to demonstrate that the Y chromosome was associated with testicular differentiation in human intersex gonads. These workers determined that XO humans, unlike fruit flies, are female. Also, no matter what the dosage of the X chromosome, the presence of a Y chromosome was sufficient to determine maleness since 47 XXY, 48 XXYY, 48 XXXY, and 49 XXXXY individuals underwent testicular differentiation. It is now recognized that differences in Drosophila and human sex determination were first glimpses at a wide array of sex determination mechanisms that have evolved independently in different species (for reviews, see Refs. 14, 77, 151, 213). For example, many animals use environmental cues such as crowding, pH, and, as proposed by Aristotle, temperature. Birds use a chromosomal sex determination system where steroids play an important role and can reverse chromosomal sex determination. Unlike humans and flies, birds are heterogametic for the female sex rather than the male (ZW female vs. ZZ male), whereas fish such as the Japanese Medaka have chromosomal sex determination where the male-determining Y chromosome is morphologically indistinguishable from its pairing partner; it is thought that the inability to distinguish X and Y chromosomes in Medaka reflects recent evolution of a chromosomal sex-determining mechanism from an ancestral pair of autosomes (3, 392). One fish, the Atlantic Silverside, actually uses chromosomes to determine sex in part of its geographic range, while using temperature to determine its sex in another part (68). In mammals, the requirement for the Y chromosome to achieve testicular differentiation suggested the existence of a Y chromosomal gene responsible for inducing the state of maleness, termed the testis-determining factor (TDF). Subsequently, the search for the TDF was narrowed to the short arm of the Y by cytogenetic analysis of abnormal Y chromosomes. Loss of the Y long arm or formation of an isochromosome consisting of duplicated short arms without any long arm material was compatible with male development, whereas in contrast, isochromosomes consisting exclusively of long arm material showed female phenotype (206). Although male-specific histocompatibility H-Y antigen looked promising as the TDF (429), both men and mice (278) were found who possessed testes but lacked H-Y antigen, and thus, the search for TDF continued. Gene mapping studies on the Y chromosome presented unique problems due to the distinct properties of three types of genetic material present on the Y. The first, the pseudoautosomal regions (PARS), located at the tips of the short and long arms of the Y chromosome (109, 129, 146, 316), contain DNA shared between both the X and Y sex chromosomes (see Fig. 1). Pseudoautosomal regions are needed to guide correct pairing and segregation of the sex chromosomes during male meiosis (134, 290). Unique among chromosome partners, the sex chromosomes form a synaptonemal complex at their tips rather than at their centromeres, and while paired, a single X-Y recombination almost always occurs within the Y short-arm PAR (41, 351, 377). The long-arm PAR is smaller than the short-arm PAR, <500 kb in length. XY recombination or gene conversion in the long-arm PAR is rare, present in only 4% of male meioses (129). Recombination maps of the Y chromosome were developed (439) based on recombination frequencies in the short-arm PAR region.
The second type of genetic material on the Y chromosome consists of repetitive satellite DNA visible by special staining. Because the satellite DNA of one species will not cross-hybridize with the satellite DNA of another, these regions are not thought to have any function (374). In fact, up to 70% of human, mouse, and Drosophila Y DNA consists of repeated DNA (70), and sex determination proceeds normally when the distal long arm of the human Y is deleted (262), showing that this region harbors no information necessary for sex determination. The third type of Y genetic material is unique Y chromosomal DNA that does not undergo recombination with the X chromosome. It is in this unique Y DNA that the TDF is located. Unique Y region DNA cannot be analyzed by traditional genetic methods that depend on recombination frequency to determine the distance between loci; instead, the unique Y region can be analyzed by correlating presence of Y-specific DNA markers to Y chromosomes with cytogenetic abnormalities. Maps of the Y chromosome based on DNA hybridization (147, 449) and maps based on deletions occurring in human patients (427) were developed to assist not only in the search for the testis-determining gene, but also to facilitate study of Y genes involved in spermatogenesis (11, 16, 260, 458, 460) and to facilitate understanding of chromosome structure and function. By analysis of chromosomal translocations where Y DNA was transferred to XX phenotypic males and where Y DNA was lost by deletion in XY phenotypic females, Page et al. (318) were able to define a critical region for testis determination that was just proximal to the pseudoautosomal X-Y pairing region on the short arm of the Y, and focused their attention on a 140-kb segment that was present in one XX male (LGL203) and absent in another XY female patient (WHT1013). A highly conserved gene in this portion of the Y (called zinc-finger Y, or ZFY) encodes a zinc-finger containing DNA-binding protein that was initially thought to be the TDF (318). Evidence consistent with the assignment of ZFY as TDF included finding ZFY-related sequences on Y chromosomes of all mammals tested and finding that a ZFY-related gene, Zfy-1, was present in the mouse sex determining region, a region termed Sxr'. However, additional study revealed that ZFY could not be the TDF: a close homolog of ZFY was found on the X chromosome of eutherian mammals (361). Also, ZFY expression was found to be in germ cells, which are not required for testicular differentiation, and testes differentiation was unaffected in We/We mice that lack germ cells and lack detectable expression of Zfy-1 and Zfy-2 (234). Finally, Y-derived sequences lacking ZFY were found in four XX men (322), and the patient whose translocation led to the cloning of ZFY was found to have a more complicated DNA rearrangement than first appreciated (317), so the search for the primary sex-determining gene continued. Additional studies of XX men with Y chromosomal DNA but not ZFY permitted precise localization of the TDF. One marker probe recognized an 8.5-kb band in normal males, but hybridized to smaller DNA fragments in XX males who harbored translocated fragments of the Y chromosome. This result implied that the probe was at or near the breakpoint of the translocations and that the testes-determining gene had to lie within the region delimited by the pseudoautosomal boundary and this probe, a distance of 35 kb. A single-copy gene that encodes a protein with homology to high-mobility-group (HMG) protein nuclear transcription factors was identified within this region (156, 372) and termed SRY, for sex-determining region Y gene. At present, an overlapping set of DNA clones spanning the entire euchromatic portion of the Y chromosome has been developed (120), and the DNA sequence of the sex-determining region and pseudoautosomal boundary has been determined (444). The HMG proteins were first characterized as chromatin components with a high electrophoretic mobility in polyacrylamide gels, and sequence analysis of various HMG proteins shows that they can be grouped into three families, the HMG-14/-17 group, the HMG-1/-2 group, and the HMG-I/-Y group (44). The SRY gene belongs to the HMG-1/-2 family, and when the term HMG box is used in this review, it refers to the homologous DNA binding domain of proteins in the HMG-1/-2 family. The HMG-1/-2 DNA binding domain defines an evolutionarily ancient superfamily whose members appear in animals, plants, and yeast. The family can be subdivided into two main classes: canonical members of the family bind to non-B-DNA conformations such as B-Z junctions, stem loops, cruciforms, four-way junctions, and cisplatin-modified DNA (18, 44); however, several members of the family, including LEF-1, IRE-ABP, TCF-1, Rox1, and SRY itself, bind to closely related variants of the A/T A/T C A A A/T G DNA motif with sequence specificity independent of any known requirement for DNA conformation (80, 141, 167, 171, 300, 413). Several lines of evidence support the role of SRY as the TDF. In a line of XY sex-reversed female mice, the SRY gene is deleted from the defective Y chromosome (156). Also, the phenotype of XX mice transgenic for a 14-kb EcoR I fragment containing the mouse Sry locus recapitulates maleness. About 30% of these XXSry mice develop testes and secondary somatic sex characteristics and exhibit male mating behavior (235). The fact that not all XXSry transgenic mice exhibit sex reversal implies that dosage and timing of Sry expression are critical for its effects, and these parameters may be subject to variation depending on the insertion site of the transgene. Indeed, human and mouse Y chromosome deletions that leave the Sry ORF intact but remove sequence including the members of the multicopy ribosomal binding motif (Rbm) gene family (260) between Sry and the centromere result in sex reversal as a result of decreased urogenital ridge expression of Sry (50, 244, 275). The decrease in Sry expression is hypothesized to be the result of an increase in proximity of the Sry gene to transcription-repressing effects of a centromere-associated chromatin domain. SRY is appropriately present in the gonadal primordia at the outset of sexual differentiation. The most precise ontogeny studies have been performed in mice, where Sry can be detected by reverse transcription (RT)-polymerase chain reaction (PCR) and ribonuclease (RNase) protection between embryonic days 10.5 and 12.5 (161, 236, 245, 350). Expression of Sry was not dependent on the presence of primordial germ cells (236). It is interesting that the initiation of SRY transcription occurs subsequent to the condensation of cells that form the urogenital ridge by embryonic day 10. Presumably, an additional regulatory system is in place to orchestrate the initial epithelial-mesenchymal transition that begins the formation of the indeterminate gonad (161). That precise control of Sry expression is needed is attested to by the presence of three ATGs in the 5'-untranslated region of the SRY mRNA and four copies of an AUUUA sequence reminiscent of the Shaw and Kamen destabilizer (367) in the 3'-untranslated region (161). These features may serve to limit the expression of the rare SRY mRNA by regulating translation and mRNA stability, respectively. After birth, Sry is again transcribed in round spermatids of the adult testis, where Sry is expressed as a circular mRNA. The circular form is thought to be favored, since surrounding genomic sequences 5' and 3' to the open reading frame are repetitive elements that share homology and could mediate base-pairing to form an RNA-RNA duplex. Circular transcripts are not translated, since no Sry protein can be detected in round spermatids (51). Expression of Sry in round spermatids is not essential for their development, since male mice lacking Sry were fertile (255). This is true for other species as well, for example, the creeping vole, which eliminates the entire Y chromosome in the germ line (309). Expression of SRY has also been detected by RT-PCR but not by RNase protection at an additional site in mice, the preimplantation blastocyst (34, 46, 135, 161, 465). Although it was originally suggested that Sry expression might account for the faster growth rate (greater numbers of somites and greater weights at equivalent days post coitum) seen for male compared with female embryonic mice, these early sex dimorphisms are unperturbed by removal of Sry from the mouse strain 129 Y chromosome. In addition, XO fetuses have a growth advantage over XX fetuses, suggesting a contribution of an X-linked locus that acts to repress size to early embryonic sexual dimorphism before onset of gonadal differentiation (43). Further work is needed to examine various X- and/or Y-linked candidate genes to define at the molecular level the locus or loci responsible for this phenomenon. In nonrodent species, SRY exhibits much less tissue specificity. All fetal human tissues examined expressed SRY, and in adult males, heart, liver, kidney, and testis showed SRY expression by RT-PCR analysis (63). SRY is also expressed in HepG2 and NTERA-2 cl.D1 cell lines, derived from adult tissues that express SRY (63). The significance of widespread SRY expression is unclear. Indeed, in the tammar wallabee, Sry expression begins at the time the gonadal primordium is present, 4 days before an increase in cytoplasmic-to-nuclear ratio heralds the onset of Sertoli cell differentiation (173). The long time delay between expression of SRY and differentiation of Sertoli cells suggests the presence of auxiliary autosomal or Y-linked factors in marsupials necessary to cooperate with SRY to regulate gonadal sex. Like human SRY, wallabee Sry is expressed in many fetal and several adult tissues including brain; these results make possible a widespread role for Sry in development of mammals. Certain Old World rodents have multiple copies of the Sry gene (298); it is unknown whether all these copies are transcribed or if some have been recruited for additional roles in development. Two rat Sry transcripts of distinct size and quantity are present in urogenital ridge cell lines (Haqq et al., unpublished data). SRY cannot be the only genetic switch molecule involved in mammalian sex development; rather, a cascade of molecules seems to be operating. For example, the wood lemming has three sex chromosomes, an X, a Y, and a modified X*, which functions to suppress the action of the Y (127). Even more striking, Sry is absent from the voles Ellobius lutescens and Ellobius tancrei, which have no Y chromosome (222). In these species, the X remains unpaired in male meiosis, making their mechanism of sex determination an interesting topic for future investigation. Furthermore, in marsupial mammals where the Y chromosome determines gonadal sex, many sexual determinants such as scrotum versus pouch formation occur before differentiation of the gonads (307), under control of a separate system based on the ratio of X chromosomes to autosomes (366). Further investigations in these model systems promise to lead to identification of additional sex-determining molecules, and it will be interesting to see how Y-determining and X to autosome-determining systems can coexist. The differential diagnosis of patients who are 46, XY but have female characteristics includes deficiency of testosterone or its 5 In pure gonadal dysgenesis, both gonads are frequently streaks, and the height of patients is normal, in contrast to the 45, XO Turner syndrome where patients have short stature, webbed neck, cardiac defects, and dorsal pedal edema. The short stature of Turner patients is likely due to a Y long-arm gene mapped between Y intervals 4B and 5G that influences height (355); this gene may or may not be identical to a Y long-arm gene that plays a role in tooth size (5a). In addition, Mutation of SRY is the first molecular explanation for the syndrome of 46, XY pure gonadal dysgenesis. As of March 1995, nearly 20 mutations in human SRY have been described (see Fig. 2 for an overview of 46 XY female patient mutations and mutations involved in SRY DNA binding-F67A and I68F; Refs. 27, 36, 176, 177, 182, 209, 274, 295, 337, 385, 424, 425). Most of these mutations lie within the region of homology to the conserved HMG box DNA binding domain, with the exception of one COOH-terminal mutation resulting in premature termination of the SRY open reading frame 41 amino acids short of the full-length protein (385). The recent finding that the COOH-termimal region binds a novel PDZ domain-containing protein, SRY-interacting protein-1 (SIP-1) (336), adds to the significance of this mutation. The fact that only 15% of 46, XY pure gonadal dysgenesis patients have an SRY mutation suggests that SRY is only one of several genetic loci whose mutation can lead to an identical phenotype. The etiology of the remaining patients must be due to mutations in genes that affect the expression of SRY itself or that play independent roles in a cascade of regulatory events specifying gonadal development.
In addition to the group of 46, XY sex-reversed females, there exists the converse type of sex reversal where 46, XX individuals display a masculinized phenotype. The bulk of such patients now come to medical attention in infancy, suffering the effects of steroid biosynthetic defects leading to congenital adrenal hyperplasia, which is discussed in section VIIID. This is distinguished from true hermaphrodites, 90% of whom are 46, XX with a mixture of ovarian and testicular tissue either on different sides of the body or within a single gonad, or rarely bilateral testes (81, 113, 163, 251). True hermaphrodites come to attention during infancy due to ambiguous genitalia (97), or later in life due to infertility. A high incidence of true hermaphroditism occurs in African Bantu tribal nations (416). Gonadoblastoma is not a frequent finding (2.6%; Ref. 416) in true hermaphrodites, even those who have inherited Y DNA, presumably because the gonadoblastoma susceptibility region is not always coinherited with the SRY locus (163). Likewise, reports of rare paternity may correlate with translocation of sufficient Y material to include spermatogenesis loci along with the testis-determining locus. SRY translocation to the X chromosome or an autosome accounts for ~30% of true hermaphrodites (163, 251). Genotype-phenotype correlation shows that individuals with SRY translocations have normal male external genitalia, whereas those without SRY present genital ambiguity (113, 306). Although mosaicism with a Y-bearing cell line could explain remaining cases of true hermaphroditism, there is a dearth of supporting evidence, and it is likely that the bulk of cases arise from mutations of autosomal loci important to sex differentiation. SRY must act to control the process of gonad formation. Normally, differentiation of the gonadal primordium into male Sertoli and Leydig cells depends on the presence of SRY and the Y chromosome (41; reviewed in Ref. 48). However, the requirement is not absolute, and there are certain situations in which male differentiation can occur in the absence of the Y. For example, XX gonadal primordia transplanted under the kidney capsule of adult male hosts develop into ovotestes (391). In these experiments, XX Sertoli cell development is delayed by 7 days relative to XY Sertoli cells. Sertoli development requires contact with the host tissue (390), and Müllerian inhibiting substance (MIS) is produced concomitant with loss of germ cells in the resulting ovotestes (389). The embryological origin of Sertoli and Leydig cell precursors is not well understood. In light and electron microscopic studies, both contributions from coelomic epithelium and mesonephros are implicated (357). In vivo, many connections of the convoluted mesonephric tubules continuous with the gonadal primordium are seen in both male and female mouse embryos at the earliest time studied, day 11.5 post coitum, and are extinguished by day 12.5 (225). Mesonephros-gonad connections could contribute cells that would give rise to the Sertoli cell lineage; however, RT-PCR for the linear urogenital ridge SRY transcript in microdissected day 11.5 post coitum mesonephri and gonads found expression only in the gonad proper, so if pre-Sertoli cells come from the mesonephros, they are not yet competent to express Sry (211). Experiments in organ culture using testes older than 11.5 days post coitum show cell recruitment from the mesonephros contributing to the myoid, endothelial and possible Leydig cell populations (225); in fact, placement of a semipermeable membrane between mesonephros and gonad led to the failure of further gonadal development (40, 285). Another source of mesenchyme, the hindlimb bud, is able to substitute for mesonephros in organ culture experiments, but the sex of the donor limb tissue had a marked effect on subsequent testosterone output by the putative Leydig cells (292). In our work, we have made immortalized rat gonadal cells using retrovirus to introduce the v-myc oncogene at day 14.5 post coitum (168; and Haqq et al., unpublished data). At this time, primordial Sertoli cells are condensing into cords, and myoid, Leydig, and germ cells are all present. An analysis of gene expression by RT-PCR shows that cloned cell lines from the mixture of immortal cells express urogenital ridge markers (Fig. 3, A and B). Each cell type has a distinct morphology in phase-contrast light microscopy. In experiments where two cell types were mixed together, we were intrigued to find that CH-17 cells have the ability to organize other cell types into aggregates that bear an at least superficial resemblance to early testicular cords (Fig. 3C). Much work lies ahead to develop molecular markers capable of distinguishing the various early gonadal cell types. Comparing patterns of gene expression in the urogenital cell lines described here may be a reasonable way to discover markers specific to particular early cell types present in the gonad.
SRY biochemistry provides some inroads to begin addressing the question of how this transcription factor operates to activate the events necessary to form the gonad. The 80-amino acid HMG box DNA binding domain is highly diverse, ranging in particular HMG box proteins from 72 to 83 amino acids in length and containing three Some members of each of the HMG groups are present in large quantities, bind DNA with little sequence specificity, and bind novel DNA structures including four-way junctions that are thought to be intermediates involved in DNA recombination. In contrast, the group of HMG-1/-2 box proteins to which SRY belongs possesses both sequence-specific and DNA structure-specific binding. Because mutations in SRY found in cases of XY sex reversal are located in the HMG DNA binding domain, sequence-specific DNA binding is thought to play a critical role in its sex-determining function. A similar role for structure-specific DNA recognition of four-way junction elements by SRY is unlikely, since mutations that cause sex reversal do not affect the ability of SRY to interact with four-way junction DNA (328). SRY is closely related to a family of HMG box proteins termed the SOX (Sry bOX) family, and because many SOX genes can bind the same consensus DNA target sites that SRY binds, and many are coexpressed in the same tissues as SRY, understanding the mechanism of SRY action must take into account the presence of these proteins. Homeodomain proteins, long thought to function solely by binding to DNA, have been shown to bind RNA, exerting control of translation to establish a molecular gradient during early Drosophila development (104, 347). These observations provide a precedent for families of proteins operating to control both transcription and translation. It is intriguing that one member of the HMG protein family, HMG2, can interact with the POU domain of transcription factors Oct1 and Oct2 via its HMG domain (464), causing a marked increase in the DNA binding activity of the Oct proteins. The inability of the SRY HMG domain to interact with Oct2 in parallel experiments (464) suggests that this type of protein-protein interaction is specific, and it is tempting to speculate that the SRY HMG domain may itself be a protein-protein interaction domain. The structures of SRY coding regions in various species have been evolving at a rapid rate (243, 406, 445), and little homology is present in these molecules outside of the DNA binding HMG box region. The lack of homology outside of the HMG box led to the proposal that the only important part of the SRY molecule was its HMG DNA binding domain. This hypothesis has been reconsidered since the COOH-terminal non-HMG region of the SRY molecule is changing faster than can be explained by accumulation of neutral mutations having no effect on SRY function. Instead, it seems that changes in the SRY COOH terminal must give SRY a species-specific advantage (406, 445). In support of there being a role for non-HMG box regions of SRY, a mutation in an XY female that results in deletion of the 41 most COOH-terminal amino acids has been described (385; see Fig. 2), and more recently, this region was found to bind a novel protein termed SIP-1 (336). This PDZ domain containing protein may favor protein-protein interactions in a higher order transcription complex. A. SOX Genes and Functions
SOX genes are present in several species as closely related groups of molecules, as in the Drosophila melanogaster HMG-D cluster, the mouse Sox 1 cluster, and the reptile Sox 12 cluster. Because whole families of HMG box proteins are present in single species like Drosophila and close homologs are not present in any other animal group (243), SOX genes may have rapidly adapted during evolution to subserve species-specific roles. Very little is known about the putative species-specific or tissue-specific function of the majority of the SOX genes. Expression patterns for several Sox genes have been published within the last years: Sox 1 is expressed in developing brain and testicular somatic cells (66); Sox 2 is expressed in developing brain, gut endoderm, and testicular germ cells (66, 410); and Sox 3 is expressed in developing brain, spinal cord, adrenals, liver, thymus, spleen, pancreas, and testicular somatic cells (66, 410). Because Sox 3 maps to a part of the X chromosome associated with mental retardation, Sox 3 is a candidate gene for X-linked mental retardation syndromes (383). Sox 4 is implicated as a transcription activator in lymphocytes containing a transcription activation domain that can function when fused to the DNA binding domain of GAL4 in yeast (112, 414); Sox 5 is expressed in postmeiotic germ cells (83); Sox 6 is expressed in developing brain and adult testis (71); Sox 11 is expressed in mesoderm and neuroepithelium, with highest levels concomitant with postmitotic neural differentiation (410); Sox 18 is expressed in adult heart, lung, and skeletal muscle (188); and zebrafish Sox 19 is expressed in late gastrulation stage embryos (428). Knowing that campomelic dysplasia was associated with primary gonadal dysgenesis (403a), and finding the sequence of the SRY-related gene SOX 9 (125) at the breakpoint of a patient with campomelic dysplasia, led to the realization that mutations in SOX 9 were responsible for both syndromes (401, 430). SOX 9 is expressed at the right time in the developing urogenital ridge to cooperate with SRY itself in sex determination. Ontongeny analysis of SOX 9 indicates that it is expressed at higher levels in the somatic cells of the male gonad immediately after SRY expression (291). Because these two gene products are coexpressed in the soma of the gonad in a male specific pattern, analysis of how the two interact may shed light on the mechanism of Sry action and sex determination. Alternately, it is possible that SOX 9 may be expressed in a cell type that interacts with the Sertoli cells expressing SRY, to specify competence to respond to a Sertoli cell SRY-induced signal (proposed in Ref. 47). Because SOX 9 plays an important role in the development of mesoderm-derived skeletal elements, the SOX 9 positive cell type might be the mesonephric cells that migrate into the gonad as seminiferous tubule myoid architecture is defined (40). Sox 1, Sox 3 (66), and the Sox 4-related gene IRE-ABP (M. Alexander-Bridges, personal communication) are all coexpressed with Sry and Sox 9 in somatic cells of the developing mouse gonad. One of the best clues to Sox gene function comes from homology comparison outside of the HMG box: Sox 1,2,3 and zebrafish Sox 19 share three regions of homology outside the HMG box (410, 428; see Fig. 4). A fourth non-HMG box region of homology is evident in comparisons of Sox 4 and Sox 11 (Fig. 4). We speculate that these regions of conservation define protein-nucleic acid or protein-protein interaction domains, and it will be interesting to see if they specify homotypic or heterotypic interactions.
Researchers in the SRY field can gain insight in studying SOX genes that bind to identical or very closely related binding sites in the same cell type by considering investigations of HMG box proteins in lymphocytes. For example, LEF-1 (also known as TCF-1 Thus studies aiming to understand SRY's action will need to be similarly inclusive, since more than one SOX protein can interact with its target element, and SRY protein is present at levels orders of magnitude lower than other members of this family. The question of how such factors can achieve specificity in their actions is of major importance. It has been proposed that SRY might cooperate with other transcription factors to achieve specificity (254). Some investigators have suggested that SRY may cooperate with AP-1-type transcription factors (64). In support of such models, Sox 2 is required to cooperate with Oct-3 at a fibroblast growth factor-4 enhancer that is active in embryonal carcinoma cell lines (457). Specificity of this interaction was apparent, since Sox 5 and Oct-2 were unable to substitute in cotransfection assays. These assays suggest that SRY can only activate in a specific context of combined binding sites. Posttranslational modification of SRY might modify the activity of SOX proteins. TCF-1 B. Factors Involved in MIS Regulation
The biology of the MIS is reviewed in detail in section VIIIA. Here, we consider the interaction of SRY and MIS, a logical putative downstream target of Sry activity, since MIS transcription begins within 20 h of Sry expression in mouse urogenital ridge (161) and is male specific until MIS transcription begins after birth (reviewed in Ref. 159). We determined that the bacterially expressed HMG domain of human SRY could protect the human MIS promoter in deoxyribonuclease (DNase) footprint assays with a nanomolar dissociation constant (167), and we and others (167, 170) determined that SRY binding to human MIS promoter nucleotides Human SRY does not have a transcription activation domain detectable by fusing SRY to the DNA-binding domain of GAL4; in contrast, mouse Sry possesses a COOH-terminal domain that has activity in transcription activation when fused to the DNA binding domain of GAL4 and transfected with a reporter containing GAL4 promoter sites (103). In a male urogenital ridge cell line, CH-34, cotransfection of an expression vector directing synthesis of human SRY with an MIS reporter plasmid resulted in a dramatic induction of transcription (168). This activation appeared to be specific, since no activation was seen for the Rous sarcoma virus LTR promoter or the mouse actin promoter (Fig. 5A).
In addition, the response of the transfection system to SRY is highly specific at the protein level. We find that SRY is the only HMG protein able to greatly activate the human MIS promoter reporter constructs; HMG-2 and LEF-1 are incapable of upregulating in our assay when equal amounts of expression plasmid are transfected. IRE-ABP gives upregulation of the reporter to levels only about one-tenth those achieved with SRY, and Sox 2 transfected in our assay leads to a strong repression of MIS transcription (Fig. 5B). Mouse SRY (data not shown) was also unable to activate the human SRY reporter in this assay. Ongoing experiments should address the question of whether SRY and other HMG proteins known to be expressed in the urogenital ridge might exhibit synergism or antagonism, but specificity with the Sox gene family. C. Mutated SRY From Sex-Reversed Patients Fails
to Activate MIS
Mutated SRY protein I68T found in an XY sex-reversed phenotypic female had diminished DNA binding activity in bandshift assays and failed to activate transcription of the reporter plasmid (168). Biophysical analysis of the interaction of this mutant protein I68T led to the identification of a hydrophobic wedge that intercalates between adjacent A-A base pairs in SRY binding sites (168, 230, 253, 441, 442; Ukiyama et al., unpublished data; Fig. 6A). An analogous mechanism of nucleic acid recognition is used by the TATA-binding protein (228, 229), the Hae III methyltransferase (342), and PurR (363), DNA-binding proteins belonging to diverse gene families, suggesting that this mechanism is widely utilized.
Nuclear magnetic resonance structure determination has defined the four residues M64, F67, I68, and W98 that constitute the hydrophobic wedge, which is conserved in many HMG box sequences (442; Fig. 6B), and we have now extended our analysis of defective SRY proteins to include hydrophobic wedge mutants M64I, M64A, F67A, I68T, and W98R. Three of these mutants, M64I, I68T, and W98R, are clinically associated with sex reversal. Mutants M64A, F67A, and I68T are well folded after synthesis in Escherichia coli, and all show decreased affinity in DNA-binding gel-shift assays (E. Ukiyama, C. Haqq, Y. Morikawa, M. Weiss, and P. Donahoe, unpublished data). W98R fails to fold properly and was therefore excluded from further analysis. Figure 6C presents an analysis of transcriptional activation by mutant SRY proteins M64A, M64I, F67A, and I68T assayed by transient cotransfection of mutant SRY molecules with MIS-luciferase reporter plasmids in urogenital ridge cell line CH-34. All mutations of hydrophobic wedge positions resulted in substantial loss of transcription response. Mutation of the isoleucine-68 to threonine results in 50-fold decreased DNA binding and lack of transcription response (168; Fig. 6C). Because isoleucine-68 is the position that plays an important structural role in DNA binding by intercalation into a widened minor groove, the lack of transcription seen when the mutant protein is transfected into cells proves that DNA binding activity is necessary for SRY to show upregulation in the assay, arguing against artifactual transcription due to nonspecific protein-protein interactions. Although mutation of the first hydrophobic wedge position, methionine-64 to alanine, results in abolition of the transcription response, mutant protein M64I, which is associated with sex reversal clinically, had partial activity in the transfection assay. Analysis at this position again demonstrates a tight correlation of SRY activity in the transfection assay with biochemical analysis. Previous investigation of the M64I mutation showed that the DNA binding activity was largely intact (<2-fold decrement in DNA binding affinity; Refs. 171, 334; Ukiyama et al., unpublished data), but that the angle induced upon DNA binding was greatly altered (334). For this reason, it was proposed that a defect in DNA bending was the explanation for sex reversal with the M64I mutation. However, recent results prompt reevaluation of this hypothesis. Our group has determined that the decrement in DNA bending by the M64I mutation is only 30° (Ukiyama et al., unpublished data). We believe the difference stems from lengths of the bacterially expressed SRY HMG domains used by the two groups, the former using 77 amino acids that did not include the basic domain just COOH terminal to the classic HMG box, wherease the latter used an 85-amino acid protein that did include this region. The TCF-1 and LEF-1 basic region contributes to DNA binding and DNA bending (253, 341). Experiments are now under way to compare protein-induced DNA bend angles in the identical experimental assay with the two lengths of SRY peptides. Changes in SRY protein-induced DNA bend angle are unlikely to be responsible for the diminished biological activity of the M64I molecule, unless the cotransfection assay is sensitive to changes in bend angle of only 30°. D. Superactivator SRY Isoleucine 68 Phenylalanine
We reasoned that the hydrophobic wedge of SRY might not be optimal for intercalation into the minor groove and interruption of base stacking, since the isoleucine at position 68 is considerably less hydrophobic than the phenylalanine present at the analogous position of other HMG proteins, including chimpanzee Sry. We predicted that if we replaced the isoleucine-68 position of SRY in the hydrophobic wedge with phenylalanine, we could make a superactive SRY molecule. In fact, cotransfected SRY I68F yields more activation than wild-type SRY when equal concentrations of expression vectors are cotransfected (Fig. 6D). High concentrations of SRY I68F yield a maximal activation that is at least four times higher than wild type, and 16 times higher than M64I (data not shown), suggesting a qualitative gain of function in this mutant. Future studies using this superactivating I68F mutant molecule may be able to shed light on the mechanism of transcription stimulation by SRY. E. Functional Mapping of the MIS Promoter Response to SRY
Analysis of deletion constructs of the human MIS promoter showed that coexpressed SRY was able to stimulate even very small fragments of the MIS promoter as long as they contained the start site for transcription. However, the quantitative amount of SRY-induced transcription was greatly reduced by each deletion. The fact that the smallest fragments that do not contain a binding site for SRY still upregulated suggested that the cotransfection system might be biased because of SRY binding to sites within the vector itself (Morikawa et al., unpublished data). In support of this, empty reporter vector without an MIS promoter insert could be stimulated by transfection of large amounts of SRY. Sox 18's transactivation properties include the same activation of the empty reporter vector, with further transcription resulting from ATTGTT sites placed upstream of a minimal promoter (188). To our knowledge, all available chloramphenical acetyltransferase, growth hormone, and luciferase reporter vectors used for these experiments contain the simian virus 40 (SV40) polyadenylation signal in multiple tandem copies just 5' to the promoter cloning site, and each SV40 polyadenylation signal contains a perfect ATTGTT match to the consensus site for binding of SRY and SOX proteins; however, reporter vectors that use polyadenylation signals without these ATTGTT sites continued to upregulate in this assay (T. Clarke and P. Donahoe, unpublished data). Until the reporter vectors are purged of ATTGTT sites, it will not be clear whether SRY acts directly at SRY as suggested by DNase footprint analysis, or whether SRY induces expression of another factor which in turn acts to upregulate MIS transcription. It will also be interesting for future experiments to address the role of SRY in transgenic mice, since the detailed chromatin configuration of the MIS promoter in host chromosomes compared with the plasmids used in transient transfection analysis might be different enough to show distinct effects on MIS transcription. Analysis of MIS initiator region (MIS-InR), We previously demonstrated that SRY could bind to and protect sites in the rat aromatase P-450 promoter (167). Although aromatase is important to female sexual differentiation, aromatase transcription is seen in mouse fetal ovaries and testes without sex specificity (245); on the other hand, no aromatase activity is detected in rat ovaries during fetal life (440) and expression of aromatase in the brain appears to be highly sex specific during fetal life (193). Although human SRY upregulated a This assay developed for human SRY and the MIS promoter (168) along with assays developed for SRY and the fra-1 promoter (64) and for mouse Sry and reporters containing the consensus binding element (103) are the first assays available to test function of the SRY molecules. We have used our assay to demonstrate that SRY mutations associated with sex reversal in humans demonstrate defects in transcription activity of the MIS promoter (see Figs. 2 and 6). F. Additional Factors Involved in Regulation
of the MIS Promoter
Recent cloning of the mouse (296), rat (166), and chicken (111) MIS genes, along with promoter sequencing upstream of the human and bovine genes (54, 55, 157), now permits precise studies of the regulation of MIS expression in efforts to define transcription factors whose activity may work with SRY or downstream of it in the pathway leading to male sexual differentiation. The 5'-region upstream of MIS is notable for its close proximity to the transcription unit for a spliceosome-associated protein (SAP62), which is transcribed with the same orientation as the MIS gene (100). In mouse, SAP62 transcripts use a polyadenylation signal at A MIS promoter element termed MIS-RE-1 (368), or M2 (human MIS nucleotides Although the above results suggest that SF-1 may play a role in MIS transcription, SF-1 is present in the ovaries from embryonic days 13.5 to 16.5 (199), a period when ovaries never express MIS (296). Thus, if SF-1 is responsible for regulation of the MIS promoter in vivo, additional tissue and sex-specific factors, possibly including the SF-1 hormone binding domain ligand, must preclude SF-1 from acting at this time. Homozygous disruption of the SF-1 gene in mice leads to a phenotype where gonad and adrenal development fails before the stage of MIS transcription (257), so this knock-out cannot help determine whether SF-1 is involved in MIS transcription in vivo. An alternative hypothesis to explain these findings is that additional factors can bind at the MIS-RE-1/M2 site to cause MIS transcription. The M2/MIS-RE-1 sequence containing the binding site for SF-1 (6 bp) is part of a larger region of evolutionary conservation across species (12 bp), and when the entire 12-base element is used for gel-shift experiments using testicular or ovarian nuclear extracts, the pattern of specific DNA-binding activities detected is complex. In addition to three male specific bands of distinct migration, female-specific ovarian gel shifts are present concomitant with ovarian MIS expression (Fig. 7A). We believe these gel shifts are due to the granulosa cell compartment, since they were detected in nuclear extract from a clinical granulosa cell tumor specimen (Haqq et al., unpublished data). Our laboratory is in the process of purifying an ~20 kDa M2-DNA binding activity (Fig. 7B) distinct in molecular weight compared with 51-kDa SF-1 from newborn bovine testes. This M2 binding protein might modify SF-1's transcription activity, or might exert its transcription influence independent from SF-1. It is equally important, however, to rule out that this NH2-terminally blocked band (Haqq et al., unpublished data) is not merely an enzymatically induced fragment of SF-1.
Full-length copies of SRY have been obtained from mouse, human (372), rabbit (445), bovine (79), and rat (Haqq et al., unpublished data) species. In addition, partial clones of SRY from many other species have been obtained by PCR amplification of their HMG DNA binding domains (72, 124). Several notable species-specific differences exist in the organization of the SRY locus, the structure of the gene itself, and the function of the expressed protein in transgenic mice and in biochemical assays. The putative promoter region of the SRY gene contains multiple potential SP1 binding sites, as well as possible autoregulatory binding sites for SRY itself. However, the human SRY promoter lacks a TATA box, which is present in all other species. Transcription start sites have been mapped for human SRY by two groups. One group expressed human SRY in a mouse cell line finding two different start sites for SRY transcription at Finding that Sry as a transgene can make XX female mice develop as males indicates that most if not all downstream genes in the sex determination pathway are autosomal. Two autosomal gene products, testosterone and MIS, are well-characterized modulators of the sexual phenotype and are discussed in separate sections below. DAX-1, an orphan member of the steroid hormone transcription factor family related to steroidogenic factor 1, is responsible for adrenal hypoplasia congenita (297, 459). In patients with adrenal hypoplasia congenita, hypogonadotrophic hypogonadism results from the defect in pituitary-gonadal-adrenal endocrine axis. DAX-1 maps to the same region of the X chromosome that is associated with male to female sex reversal when it is duplicated (26, 308, 360, 381); other duplications of Xp that do not give rise to sex reversal were used to limit the critical interval to Xp21.3-22.11 (16, 241, 299). The sex reversal function is named dosage-sensitive sex reversal (DSS) (297), and it is possible that DSS and DAX-1 are identical. However, other genes are present in the critical region of Xp21, so further experiments are needed to address the timing and tissue specificity of DAX-1 expression, whether the gene is subject to X-inactivation, and whether duplicated DAX-1 in transgenic animals gives the same phenotype as DSS. It will clarify matters greatly if molecular target genes downstream of DAX-1 are identified. Masafumi and Jameson (264) recently discovered a direct interaction between DAX-1 and SF-1 which resulted in inhibition of expression of SF-1 heterologous and homologous reporter constructs. A. MIS and Sex Differentiation
Every normal person, XX or XY, has the potential to develop both male and female reproductive structures. During fetal life either the Wolffian or the Müllerian duct must develop while the other must regress in response to differentiation of bipotential gonads into either testes or ovaries. Professor Alfred Jost, in the late 1940s, first discovered that the influence of the testis on male development required two hormones (219). Jost surgically removed the gonads of fetal rabbits during various stages of sexual differentiation. Removal of either testes or ovaries before, or at the outset of gonadal differentiation, resulted in female somatic development, the Wolffian ducts regressed instead of going on to form the vas deferens and seminiferous tubules, while the Müllerian ducts persisted and developed into the oviducts, uterus, and upper vagina. When Jost transplanted a testis into a female fetus, Müllerian ducts were inhibited and Wolffian ducts persisted. The converse transplant of ovary to male had no effect. Finally, when a crystal of synthetic androgen, instead of an entire testis, was placed in the abdomen of a castrated male, Wolffian development was supported but the Müllerian system failed to regress. Therefore, Jost (219, 220) postulated the existence of two hormones, one an androgen that would support male Wolffian duct development and a second called l'hormone inhibitrice or the Müllerian inhibitor, responsible for regression of developing female Müllerian structures. L'hormone inhibitrice, later called MIS (217) or anti-Müllerian hormone (AMH), was subsequently found to be a Sertoli cell protein (32). It was purified to homogeneity (38, 39, 331), and both bovine and human MIS genes were cloned (54, 332). Müllerian inhibiting substance is one protein of a large superfamily whose members play key roles in development, wound healing, suppression of tumor growth, and feedback control of the pituitary-gonadal hormone axis. Related proteins include transforming growth factor- Cloning of MIS with subsequent investigations has confirmed Jost's foresight and enabled novel observations of MIS activities that suggest additional roles. Overexpression of MIS in transgenic female mice resulted in a phenotype characterized by regression of Müllerian ducts as predicted by Jost's experiments (20). However, the ovaries of these female mice exposed to supraphysiological levels of MIS became depleted of germ cells and formed structures reminiscent of seminiferous tubules. Mutation of the MIS gene is associated with the persistent Müllerian duct syndrome (52, 200, 233). Surprisingly, many of these mutations are located in the NH2 terminal of MIS, whose role in bioactivity is not fully understood (447). Enzyme-linked immunosorbent assay detection of mutant protein levels are lower than wild type, perhaps indicating that these mutations affect translatability or stability of the protein; however, the same result would hold if the mutations interfered with recognition by the antisera, so further work will be required to show the precise molecular mechanism for these mutations leading to the persistent Müllerian duct syndrome. One-fourth of male mice exposed to supraphysiological levels of human MIS showed feminized testes and external genitalia (20). Thus MIS may play a role in the formation of gonadal and external genital structure, perhaps by affecting expression or function of the androgen receptor in target tissues. Catlin et al. (56, 57) have shown that MIS decreases levels of disaturated phosphatidlycholine, the major component of surfactant in fetal lungs, which led to the hypothesis that MIS may contribute to the male preponderance in newborn infants of respiratory distress syndrome. Finally, the role of MIS as a negative growth regulator in fetal life suggested that MIS might have antitumor activity against neoplastic cells, especially those derived from Müllerian duct structures. These effects were apparent for ovarian and uterine carcinoma cell lines (61, 98) and primary tumors (133). In whole animal experiments conducted in nude mice, recombinant human MIS had potent inhibitory activity against the growth and reduced the number of metastases of an ocular melanoma (323). Homozygous deletion of the MIS gene resulted in male mice with retained Müllerian ducts. Female MIS To address the question of whether redundancy of a related molecule might be masking some expected phenotypes of the homozygous MIS-deficient mice, mice doubly deficient in both MIS and the related Sertoli cell product inhibin were constructed. B. Mutation of the MIS Type II Receptor and MIS Receptor Signal Transduction
Results consistent with the identification of the MIS type II receptor (13, 87, 88, 396, 426) come from identification of a receptor mutation that leads to the persistent Müllerian duct syndrome. Mutation of the 5'-splice donor site for intron 2 led to aberrant splicing of the gene product in mRNA prepared from a biopsy of testicular tissue (201). Confirmation of the developmental role of this type II receptor was proven by the homozygous knock-out of the mouse receptor, which showed the phenotypes of retained Müllerian ducts, almost identical to that caused by the ligand knock-out (289). The family of transforming growth factor- C. Role of Androgens and Sex Steroids
in Sex Differentiation
Normal androgen action is essential for male anatomic sex differentiation and reproductive function. Hereditary defects that diminish androgen action in chromosomal males or that increase androgen action in chromosomal female patients result in the most frequently diagnosed disorders of sexual differentiation (reviewed in Refs. 93, 154). Leydig cells, induced to differentiate by SRY-expressing fetal Sertoli cells, are an essential site of testosterone biosynthesis during male differentiation. Testosterone is synthesized from cholesterol through the activities of side chain cleavage, 3 D. Defects in Steroid Biosynthesis Lead
to an Intersex Phenotype and Congenital
Adrenal Hyperplasia
Defects in testosterone biosynthesis result in a phenotype with a male gonad but incompletely masculinized Wolffian duct structures and/or external genitalia, termed male pseudohermaphroditism. Female pseudohermaphroditism may occur when defects in enzymes leading to glucocorticoids and mineralocorticoids are present, leading to shunting of precursor molecules into the androgenic pathway, or when defects in estrogen formation are present. The defects in steroid biosynthesis, their clinical diagnosis, and management have been recently reviewed (93). CYP21 21-hydroxylase deficiency has the greatest clinical significance, accounting for >90% of steroid biosynthetic defects, with an incidence between 1:10,000 and 1:18,000 live births (93). Mutation of CYP21 results in the clinical syndrome of congenital adrenal hyperplasia, a form of female pseudohermaphroditism due to insufficient mineralocorticoid and precursor shunting into the androgenic pathway. Because the CYP21 gene and a pseudogene CYP21P lie together in close proximity, unequal crossing over and gene conversion events in addition to point mutations are the molecular basis of 21-hydroxylase deficiency (for example, Ref. 92). CYP11B1 11 Mutations in 3 Defects in P-450 aromatase render patients unable to convert precursors to the female sex steroids estradiol, estrone, and estriol. Only a handful of patients have been described with this syndrome of female pseudohermaphroditism. However, a partial deficiency seems to be more common and may account for some fraction of women with polycystic ovaries due to hypergonadotropic stimulation in the absence of estrogen to cause negative feedback at the hypothalamus (69). More marked effects of aromatase deficiency during fetal life may be masked by maternal expression of placental aromatase, resulting in sufficient female sex steroids during fetal life. A defect in regulation of the steroidogenic genes, rather than mutations of the enzymes themselves, is likely to cause additional defects in steroid biosynthesis. Several steroidogenic genes are known to be regulated by SF-1 (also called ADBP4), a member of the steroid hormone receptor family of transcription factors that binds DNA as a monomer (186, 198). SF-1 is an orphan receptor, since the ligand that binds its hormone binding domain has not yet been identified. SF-1 binds to a common DNA sequence present in the promoters of P-450scc, P-450c11, P-450c21, P-450c17 and P-450 aromatase (259, 294). However, P-450c11 and P-450c21 are expressed in adrenals but not gonads, whereas P-450 aromatase is expressed in gonads and not adrenals despite the fact that SF-1 is expressed in both organs (199). This suggests there are as yet unidentified factors limiting tissue-specific expression or activation of these genes (305). E. Defects in the Androgen Receptor Lead
to Testicular Feminization
The two predominant androgens in humans, testosterone and dihydrotestosterone, both bind the same receptor protein. The receptor-testosterone complex signals to support differentiation of the Wolffian duct during embryonic life, regulation of secretion of lutenizing hormone by the hypothalamic-pituitary axis, and spermatogenesis. The receptor-dihydrotestosterone complex promotes development of the external genitalia and prostate during embryogenesis and also is responsible for pubertal changes including growth of the adult hair pattern, temporal hair recession, and maturation of the external genitalia and has been suggested to regulate male-specific behavior. The reason for distinct responses to the two hormones binding the same receptor may be due to difference in binding affinity (dihydrotestosterone has higher affinity for the androgen receptor) or a qualitative effect on receptor function (receptor-dihydrotestosterone is able to activate reporter gene constructs more easily; reviewed in Ref. 154). The androgen receptor, a member of the steroid receptor superfamily, is an X-linked locus in humans whose complete deficiency leads to the syndrome of testicular feminization, or complete androgen insensitivity (58, 256, 400). Patients with testicular feminization tend to be taller than average women, and tooth size is as large as normal men (6, 417), as can be explained by the fact that they have Y chromosomal genes described above. Some mutations in the androgen receptor do not completely inactivate the receptor and thus lead to deficient but not completely absent masculinization. Patients with Reifenstein syndrome (280) show the phenotype of these defects. A rare class of testicular feminization patients may result from Leydig cell agenesis or hypoplasia that has been seen in cases consistent with autosomal recessive and dosage sensitive Y-linked inheritance (137, 354). F. Defects in Steroid 5 Patients with female external genitalia at birth, bilateral testes, and normally virilized Wolffian structures that terminate at the vagina frequently have steroid 5 G. Additional Autosomal Genes Involved
in Sex Differentiation
In XX sex reversal, first recognized by de la Chapelle et al. (81), individuals lacking a Y chromosome develop testicular tissue (25, 251, 273). Sry translocation to the X chromosome or autosomes accounts for only a fraction of such individuals. It is interesting that those XX males lacking Y-derived sequence and SRY have a high incidence of genital and gonadal ambiguity (termed XX pseudohermaphrodites), whereas those with SRY generally have normal male internal and external genitalia (1, 113, 117, 251, 306, 327). Another possibility to explain the etiology of XX maleness is mosaicism with a Y-bearing cell line, but there is limited clinical evidence to support this mechanism (113, 306). A third possibility to explain XX maleness is mutation in autosomal or X-linked (394) genes distinct from SOX 9, DAX-1, MIS, and androgen receptors, leading to a constitutive activation of a male determining gene or loss of function in a female-determining gene. Evidence for loss of function of just such an ovary-determining gene has been found in studies of familial ovarian dysgenesis (421). In humans, several syndromic conditions are associated with abnormal sexual differentiation of XY individuals; most of these involve sex reversal of XY infants to a female phenotype. They include campomelic dysplasia (discussed in sect. VIA; SOX 9), Smith-Lemli-Opitz (30), Denys-Drash (324), and X-linked There are several animal models for such conditions (105, 106, 164, 375). Seven dog breeds are known to exhibit XX sex reversal (286, 287), which might be due to SRY translocation to another chromosome or to mutations in an autosome. Meyers-Wallen and co-workers (286, 287) have shown that two of these dog breeds lack SRY sequences, and thus an autosomal mutation must be responsible for the sex reversal seen in German short-haired pointer dogs and American cocker spaniel dogs. Fertile females of the mole Talpa occidentalis are Sry-negative true hermaphrodites (212); this species likely has a gain of function of a male-determining autosomal gene active in both sexes. Finally, Eicher et al. (108) have taken a novel approach to characterize autosomal genes involved in sex determination, taking advantage of sensitizing mutations in particular mouse Sry alleles. It has been known for many years that the Y chromosome from Old World wild mice (Mus domesticus) bred into the B6 inbred lab strain derived from the house mouse (Mus musculus) causes a high incidence of XY female progeny. When studied during embryogenesis, these embryos start out with bilateral ovotestes, but the testicular elements regress over time so that the adult phenotype is a sterile XY female. Some breeding experiments produce a delay in the timing of seminiferous tubule formation by ~14 h (320, 389), which corresponds to a delay in Sertoli cell differentiation as detected by the production of MIS, assayed by immunohistochemisty or RT-PCR, in these gonads (245, 309). The interpretation is that the M. domesticus fails to interact properly with autosomal genes in the house mouse, either because of a lag in Sry expression to a period where ovary-determining signals take effect or, because of a qualitative defect in the Sry protein, to initiate normal development. To address this question, Lee and Taketo (245) used RT-PCR to study Sry expression in ovotestes, finding that onset of Sry transcription is unperturbed but that the duration of SRY expression is prolonged by >24 h, which they suggest leads to upregulation of gene transcription by a feedback mechanism due to a poor response to Sry protein. Because onset of Sry transcription is preserved in ovotestes, it is unlikely that a delay in Sry ontogeny is the only factor leading to sex reversal in this model, although levels of Sry protein have not yet been correlated with transcript levels. Future work will seek to understand what is different about M. domesticus that results in its defective function. Is the defect in the Sry gene itself, in regulatory regions surrounding Sry on the Y chromosome or even in some part of the Y chromosome, unrelated to the Sry locus?
One hypothesis is that Sry molecules from these strains have different structures. There is some evidence to support this; several strains have Sry molecules that have a premature stop codon relative to the 129 mouse strain in which Sry was first characterized. Being shorter is not thought to result in sex reversal, however, since Y chromosomes of several strains, FVB/N, SJL, and SWR/J, which have the premature stop codon do not cause sex reversal (75, 107). An additional difference in Sry molecules detected by Coward et al. (75) was the length of a trinucleotide repeat polymorphism present COOH terminal to the HMG domain. At first the number of CAG repeats appeared correlated with the function of the Sry molecules, but exceptions have been found (107), so it is thought to be possible that the CAG repeat polymorphisms reflect an additional allelic difference specific to particular mouse strains, possibly including mutations in the Sry promoter regulatory region. Formal testing of whether it is a defective Sry or some other Y-linked locus that is responsible for the development of ovotestes awaits experiments with transgenic mice where one Sry molecule can be swapped for another while keeping the rest of the Y chromosome and autosomes the same. Sry has been suggested to repress a gene that functions in the absence of the Y chromosome to initiate ovarian development (276), and efforts are underway to clone the autosomal loci that interact with Y chromosomes in a strain-specific fashion. It will be interesting to see if autosomal genes cloned by this approach fulfill this prediction, and how they play their roles in the sex determination and testicular differentiation cascade. Several genes thought to play important roles in development have expression domains including the developing urogenital system. The expression pattern of these genes during development, where known, is summarized in Figure 8. Many of these gene products could well play a role in urogenital system development. In many cases, definition of their tissue-specific roles awaits homozygous deletion of these loci by transgenic "knock-out" technology and definition of the resulting phenotypes. Recently, such evidence was found for hox genes, hoxa 10 and hoxa 11. Hoxa 10 is normally expressed in the gubernaculum, a mesenchymal band of tissue connecting the testes to the abdominal wall, in the abdominal wall, distal oviduct, uterus, and developing decidua (346, 358), whereas hoxa 11 is normally expressed in limbs, kidney, glans penis, and mesenchyme surrounding the Wolffian and Müllerian ducts (191). The hoxa 10 knock-out resulted in a phenotype of female and male infertility due to a defect in the uterine environment and a failure of testicular descent correlated with a homeotic transformation in the spinal nerves (191, 358). This is interesting in view of earlier observations by Hutson and colleagues (145) who found sexual dimorphism in the size of specific anterior horn cell spinal nuclei, whose axonal processes travel in the genitofemoral nerve. When the genitofemoral nerve is paralyzed, testicular descent fails (194). The phenotype of the hoxa 11 transgenic knock-out greatly resembled that of hoxa 10; there was a defective uterus unable to support implantation, a partial homeotic transformation of the vas deferens into a structure resembling epididymis, and a failure of testicular descent (191). Demonstration that SRY conveys the signal for maleness to the gonad of many mammals constitutes a signal advance in understanding sexual differentiation, providing insight into two types of human intersex patients, 46, XY women and 46, XX true hermaphrodites. Because many human mutations resulting in intersex abnormalities are compatible with life, the large clinical literature available makes detailed investigations possible. Many model systems are now available in mammals that promise to permit characterization of SRY, related SOX genes, and other molecules of the regulatory cascade necessary to form a testis. Insight into genes that control ovarian development is beginning to solidify around dosage-sensitive sex reversal associated with the X chromosome and study of the Turner syndrome phenotype. It is gratifying to know that experiments are currently underway that in time could systematically elucidate the entire program by which chromosomal sex is translated into phenotypic sex. We hope that, ultimately, intersex patients will be able to benefit in their clinical care from these investigations.
I. INTRODUCTION
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II. SEX-DETERMINING ROLE OF HUMAN
Y CHROMOSOME
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FIG. 1.
Schema of the X and Y chromosomes is shown during meiosis, featuring a crossover between X and Y DNA in the short-arm pseudoautosomal pairing region. Also shown is region of synaptonemal complex formation. Inset: location of SRY testis determining gene within unique Y chromosome DNA on Yp short arm.
III. IDENTIFICATION OF THE SEX-DETERMINING GENE SRY
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IV. MUTATIONS IN SRY EXPLAIN A SUBSET
OF PATIENTS WITH 46, XY PURE
GONADAL DYSGENESIS
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-reduced metabolite, defects in the androgen receptor, chromosomal mosaicism, or gene mutation resulting in failure of gonadal differentiation. Defects in the steroid hormone biosynthetic and signal transduction pathway are discussed in a section VIIIF. XY sterile females with bilateral streak gonads and sexual infantilism are said to have the pure gonadal dysgenesis syndrome, which is distinguished from the more common syndrome of mixed gonadal dysgenesis where mosaicism for 45, XO/46, XY, commonly leads to a streak gonad on one side and a testis on the other (283). 
30% of pure gonadal dysgenesis patients develop gonadoblastoma (420), a rare neoplasm containing aggregates of germ cells intermixed with a stromal component resembling immature Sertoli and granulosa cells. Because 45, XO Turner syndrome patients who also have dysgenetic gonads never develop gonadoblastoma, it has long been suspected that a Y-linked locus is responsible for gonadoblastoma, and the critical genetic region has now been mapped (404).
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FIG. 2.
Published mutations associated with female phenotype in 46, XY individuals are displayed above a schema of sex-determining SRY gene. In addition, 2 mutations not derived from sex-reversed patients, F67A and I68F, were introduced into SRY to facilitate structure-function correlation. Note that all but 1 of the mutations associated with sex reversal affect structure of SRY DNA binding domain, the high mobility group (HMG) box.
V. TRANSLOCATION OF SRY TO THE
X CHROMOSOME OR AUTOSOMES EXPLAINS A SUBSET OF PATIENTS WITH
46, XX TRUE HERMAPHRODITISM
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VI. BIOCHEMICAL ACTIVITIES OF SRY: HOW DOES SRY DETERMINE SEX?
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FIG. 3.
A: reverse transcription (RT)-polymerase chain reaction (PCR) analysis of urogenital ridge cell line RNA for WT-1 gene expression using primers indicated. B: table summarizing RT-PCR experiments to characterize expression of several urogenital ridge markers in immortalized urogenital ridge cell lines. C: ability of CH-17 cells to organize CH-23 cells but not control CH-15 cells into structures reminiscent of seminiferous tubules. CH-17 cells were able to organize other urogenital ridge cell lines including CH-4 and CH-34 into similar structures.
-helical regions. SRY's HMG box is 77 amino acids in length, of average length compared with other HMG boxes. In addition, there are no strictly conserved amino acid sequences between all members of the superfamily: only three amino acids are conserved in >80% of HMG boxes: P at position 8, W at position 45, and K at position 53 (243).
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FIG. 4.
Comparison of Sox gene sequences and identification of 3 amino acid domains of cross-species evolutionary conservation. We speculate that these domains mediate protein-protein or protein-DNA interactions. [Data from Uwanogho et al. (410) and Vriz and Lovell-Badge (428).]
) and TCF-1 are two HMG proteins present in lymphocytes that can bind the same ATTGTT consensus. LEF-1 was first characterized as a pre-B and T lymphocyte specific DNA binding protein that bound to the T-cell receptor -chain enhancer (402, 435). Subsequent studies showed LEF-1 to help assemble a multiprotein complex on the TCR- enhancer (141-143) and to be widely expressed in embryonic tissues (310). TCF-1, identified in T cells (412), was also subsequently shown to be widely expressed during embryogenesis (310) and later during development (461). In addition, the LEF-1 knock-out had no detectable immune system phenotype and rather led to striking effects on tooth, hair follicle, and mammary gland development (415), whereas the TCF-1 knock-out led to a specific phenotype in maturation of CD8+ to CD4+/CD8+ during T-cell maturation (418)./LEF-1 can activate transcription through a single copy of its response element in nonlymphoblastoid cell lines, whereas it only mediates activity of the -enhancer with intact binding sites for CREB and TCF-2 nearby in T cells (435). Similarly, GATA-1 can activate minimal promoters bearing an upstream GATA site in nonerythroid but not erythroid cells (311). This demonstrates that posttranslational modifications, or a requirement for cooperation with tissue-specific factors, restrict LEF-1 and GATA-1 activity to particular cell types. This may serve as a model for tissue-specific modulation of SOX protein activity. 
-Catenin was recently shown to interact with TCF and LEF transcription factors. The resulting constitutive gene activation can be modulated by the adenomatous polyposis coli (APC) tumor suppressor gene in APC-deficient colon carcinoma cells (293) or melanoma cells (352).
75 to 45 was diminished by nucleotide point mutations. These analyses also showed that the MIS binding site was not as high affinity a target site as SRY sites identified by PCR selection starting from random sequence (5'-ATTGTT; Refs. 168, 172). The weak nature of the SRY binding sites suggested they might be relevant only in the context of occupancy of neighboring binding sites for additional transcription factors. Thus we made cell lines from the urogenital ridge at the precise time that differentiation of the testis was in progress (168), in the hope that such lines would contain all factors necessary to transcribe the MIS promoter.
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FIG. 5.
A: cotransfection of indicated chloramphenicol acetyltransferase (CAT) reporter vectors (5 µg) with control empty expression vector pCMV (7) or expression vector directing expression of full-length human SRY (2 µg) into urogenital ridge cell line CH-34. Human Müllerian inhibiting substance (MIS) reporter vector was generated by cloning the fragment 299 to +8 generated by PCR using primers CMH-106 5'-ggg Agg CTTggCCgTCACTCCCAgCCTg and CMH-107 5'-CggAAgCTTggg TgCTgCCAggggCTg, into Hind III site of SVO-CAT (149a). Forty hours after transfection by the calcium phosphate method, cells were harvested and assayed for CAT activity by thin-layer chromatography (232). B: comparison of fold induction of 114 bp human MIS-luciferase reporter (2 µg) by SRY, LEF-1, Sox 2, IRE-ABP, or control empty expression vectors (1 µg). The 114 to +8 fragment of human MIS promoter was generated by PCR using primers CMH-128 5'-ggTACCgggCACTgTCCCCCAAgg and CMH-107. Resulting fragment was sequenced for confirmation and subcloned between Kpn I and Hind III sites of luciferase reporter pA3 (451). Although SRY was a strong activator in this assay, Sox 2 was a strong repressor, whereas IRE-ABP was a weak activator and LEF-1 had no consistent effect. Luciferase data are an average of 3 independent transfections ± SE. All transfections included 0.5 µg pXGH5, which directs expression of growth hormone under the control of a ubiquitously active promoter (364). Growth hormone determinations were used as an internal standard to control for variations in transfection efficiency.
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FIG. 6.
A: structure of SRY with the 4 amino acids M64, F67, I68, and W98 constituting the hydrophobic wedge (see text) are shown in bold. B: sequences of SRY HMG DNA binding domain and additional HMG boxes were obtained from GenBank and aligned by use of University of Wisconsin Genetics Computer Group software. Positions of amino acids whose side chains constitute hydrophobic wedge are boxed and are present within helix 1 and helix 2 of HMG structure predicted by analogy to known structures of SRY and LEF-1 (253, 441). C: transfection analysis performed as in Fig. 5B, using expression vectors encoding mutant SRY strains indicated. Luciferase data are presented as a mean of 3 independent transfections ± SE after normalization to an internal growth hormone control. All 4 mutations at hydrophobic wedge positions decreased transcription response seen in transfection assay. M64I and I68T from sex-reversed patients, as well as M64A and F67A, predicted to have defective function based on SRY structure, all show decreased transcription of 114 bp human MIS-luciferase reporter vector. Note that M64I has partial activity in assay (see text). D: transfection of a variable amount of SRY mutant I68F or wild-type expression vector (0-5 µg) with a fixed amount of 114 bp human MIS-luciferase (2 µg). Empty expression vector pCMV was used to normalize total amount of DNA present in each assay. All points on graph are means ± SE of 3 replicates, corrected for transfection efficiency using an internal growth hormone standard. SRY I68F shows a markedly enhanced ability to transactivate the 114 bp human MIS-luciferase reporter vector.
22 to +8, indicates that it is capable of mediating SRY-induced transcription. Mutation of the initiator by randomization of the 32-bp nucleotide sequence, or replacing the 3' 16 nucleotides of the MIS-InR, which contains the transcription start site, by a heterologous sequence from phage 
reduced transcription to control levels seen with empty reporter vector. In contrast, replacing the 5' 16 nucleotides of the MIS-InR with a heterologous sequence from phage had little effect. We have not been able to detect direct DNA binding of SRY to the MIS-InR region; instead, SRY may undergo protein-protein interactions with basal transcription factors bound to the InR in vivo, or might induce synthesis of basal transcription factors to high levels resulting in a secondary increase in MIS transcription levels.534 to +100 bp rat aromatase-chloramphenicol acetyltransferase promoter containing the SRY footprinted region (Fig. 5A), and cannot regulate a 227 to +100 bp aromatase-luciferase promoter lacking this region (Haqq et al., unpublished data), further work is required to see if precise mutation of the SRY footprinted region is the site of promoter regulation. Control of aromatase activity at the protein level is also possible, since it has been known for many years that MIS can downregulate aromatase enzymatic activity (423). Contributions of transcription, translation, and stability of mRNA and protein to this phenomena have not yet been distinguished.424 relative to the MIS ATG start codon; in humans, SAP62 terminates at 789. Use of an approximately 300 mouse MIS promoter fragment to drive lacZ expression in transgenic mice is sufficient to correctly initiate MIS expression in males at the same time the endogenous gene becomes active, embryonic day 12 in mice (162). However, these MIS promoter-lacZ transgenes are turned off by embryonic day 15, whereas the endogenous gene continues to be expressed in males at high levels until at least embryonic day 18. This suggests that all the information for initiation of MIS expression is contained in a very compact minimal promoter region, but that additional factors needed for maintenance of MIS expression interact with sites upstream of or within the SAP62 gene, or within MIS introns, exons, or 3'-sequence. 114 to 93 bp; Refs. 159, 169), matches the consensus sequence for an SF-1 binding site 5'-CCAAGGTCG. SF-1 rendered constitutively active by deletion of its hormone binding domain can activate the MIS promoter in Sertoli cells (368); it was proposed that a tissue-specific SF-1 ligand is present in Sertoli cells, since SF-1 responses were stronger in Sertoli cells than in extragonadal HeLa cells. Intact SF-1 in a male urogenital ridge cell line transcriptionally repressed the MIS promoter through this site (168).
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FIG. 7.
A: electrophoretic mobility shift assay of nuclear extract prepared by microdissection of tissues labeled above gel lanes at indicated times during rat embryogenesis, performed by standard protocol (128) in 5% 38:2 acrylamide-bis-acrylamide low cross-linking gels. Nuclear protein extract (10 µg), quantitated by the Bradford-Lowry assay, was used in each lane; probe was rat M2 5'-CAggCACTgTCCCCAAggTCACC annealed to its 32P-labeled complement. Control gel shifts were performed using a probe for ubiquitous protein H2TF1 (14a) and showed a robust H2TF1 gel shift in all cases, confirming integrity of all extracts. B: purification of a protein of ~22 kDa binding to M2 MIS promoter DNA element. Nuclear extracts were prepared from newborn bovine testes by modification of an established procedure (89) making nuclei in a Waring blender. Crude nuclear extract was fractionated on heparin-agarose and subsequently salt eluted, dialyzed, and subjected to 2 rounds of purification on a DNA affinity column (223) made of a support matrix bound to multimerized M2 DNA sites. Coomassie-stained 15% SDS-PAGE of affinity-purified M2 DNA binding protein (5, 10, and 25 ml) were compared with known quantities (10, 20, and 100 pmol) of the 85-amino acid SRY HMG box expressed in Escherichia coli.
VII. SRY TRANSCRIPTION UNIT: WHAT REGULATES SRY EXPRESSION?
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137 and 78 nucleotides upstream of the ATG (384). In contrast, mapping human SRY start sites using mRNA in tissues in which SRY is normally expressed reveals start sites at 91 and 501 (63). The discrepancy between start sites found in transfection experiments compared with endogenous RNA from tissue sources suggests that tissue- or species-specific factors may be involved in transcription at the SRY locus.
VIII. AUTOSOMAL AND X-LINKED GENES INVOLVED IN SEX DETERMINATION
AND DIFFERENTIATION
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(84), nodal (461a), activins (190, 250, 277, 411), inhibin (265), decapentaplegic and related molecules (90, 315), Vg-1 and related molecules (214, 359, 437), osteogenic proteins (313, 314), bone morphogenesis factors (452), cartilage-derived morphogenetic proteins (59), and growth/differentiation factors (189, 247, 277, 281). Expression studies of MIS revealed synthesis of MIS not only in fetal and neonatal males, but also in females, where MIS is first synthesized in postnatal ovarian granulosa cells that surround and nourish developing oocytes, and then produced in dynamic fashion with rising levels throughout the follicular phase, peaking just before ovulation, throughout female reproductive life (28, 296, 386, 409). Müllerian inhibiting substance is an inhibitor for several processes, including oocyte meiosis (387, 408), the production of aromatase in the fetal ovary (86, 423), and levels of aromatase and lutenizing hormone receptor in the postnatal ovary (87), and MIS blocks epidermal growth factor-induced synthesis of progesterone in postnatal granulosa cells (227), suggesting that it plays a role in the control of granulosa cell steroidogenesis. / mice were fully fertile, whereas most males were infertile due to anatomic blockage of sperm egress; in vitro fertilization with their sperm resulted in production of normal offspring (20). Newborn males showed no respiratory distress or developmental lung defects (20). These findings are surprising given the tightly regulated expression of MIS in the ovary and its proposed roles as a control factor for granulosa cell steroid production and oocyte meiosis, for architectural differentiation of the testes and male external genitalia, and for lung surfactant synthesis. To explain this enigma, it has been proposed that genes related to MIS may be present in Sertoli and granulosa cells and may be redundant for certain MIS functions, or that certain functions of MIS are species specific (20). Because MIS is known to inhibit P-450 aromatase and because a subset of mammals express P-450 aromatase in the placenta, one may speculate that MIS phenotypes with regard to effects on steroidogenesis will be found to be species specific on the basis of placental expression of aromatase activity. Mice deficient for MIS had a high incidence (27%) of Leydig cell hyperplasia on histological examination, and one animal produced a Leydig cell neoplasm, suggesting a role for MIS as a tumor suppressor gene. A putative heterodimer receptor for MIS, consisting of two transmembrane serine/threonine kinases, type I (178) and type II (13, 88, 396, 426), has been isolated. Mutation of this type II receptor, like mutation of MIS itself, is associated with persistent Müllerian duct syndrome (201), and MIS type II receptor expression appeared to be limited to Sertoli cells and mesenchymal cells surrounding the Müllerian duct in males (396). However, because Leydig cells have no MIS receptor, but experience effects of MIS as a Leydig cell tumor suppressor, localization of MIS receptors on Leydig cells deserves further study. -Inhibin-deficient mice develop focal Sertoli/granulosa cell tumors (271). Double-deficient mice lacking both MIS and -inhibin show multifocal Leydig cell hyperplasia as well as multifocal Sertoli/granulosa tumors occurring at a much earlier age than with single gene deficiencies (270), confirming the role of these molecules as tumor suppressors in vivo and showing their synergy with combined deficiency. These results point to MIS and related molecules as targets for anticancer drug development. It will be interesting to see the result of doubly deficient mice for MIS and the related oocyte-specific molecule GDF-9 (277). receptors is thought to function by the type II receptor first binding ligand, which then gives the type II receptor competence to dimerize with, or recruit, the type I receptor, which in turn is responsible for signal transduction. The intracellular domain of the putative type I MIS receptor candidate has been used as the bait in yeast interaction trap experiments that identified one of its intracellular interactors to be FKBP12, the binding substrate for the widely used immunosuppressant drugs FK506 and cyclosporin (433, 434). Subsequent studies have shown that FKBP12 is released from the type I receptors upon ligand binding, which implies that FKBP12 acts as an inhibitor of signal transduction (434). We have identified other specific cytosolic interactors with the MIS type I receptor (Wang et al., unpublished data) that are being characterized as potential positive regulators for the MIS-induced signal transduction cascade.- and 17-dehydrogenation (P-450scc, P-450c17; 3B-HSD and 17B-HSD; reviewed in Ref. 288).-hydroxylase deficiency is the next most common cause, resulting in 5% of cases (for example, Ref. 443). Rarer deficiencies of other enzymes occur: 20,22-desmolase (20,22-lyase; Ref. 338); mutations in the gene CYP11A have not yet been described at the molecular level (93). -hydroxysteroid dehydrogenase (3-HSD) are also a rare cause of insufficient masculinization; in females, the phenotype is actually related to the mild androgen excess caused by peripheral conversion of dehydroepiandosterone, one of the substrates for 3-HSD activity (371). Three genes encoding constitutive, placental, and testes-specific 17-HSD activity, respectively, have been isolated (136, 326, 397, 453). Of the three isozymes, only the type 3 testicular isozyme is responsible for the bulk of clinical 17-HSD deficiency (136). It is not clear why these patients virilize at puberty. Either there may be sufficient type I and type II activity to produce adequate testosterone in response to pubertal hypophysial signals, or an as yet undiscovered isozyme present only post puberty might exist. -Reductase Result in an Intersex Phenotype
-reductase deficiency resulting in an inability to form dihydrotestosterone (202, 431). Of the two known isoforms of this enzyme, the type II enzyme is present in the external genitalia, where dihydrotestosterone is the dominant androgen required to elongate and ventrally close the penile anlagen translocating the urethral meatus from the perineum to the tip of the penis. Cloning of the chromosome 19 gene for steroid 5-reductase 2 has permitted identification of mutations of this gene in 36 of 37 families with clinical features of the disorder (7, 398); the one family where no mutations were found within the exons is thought to have suffered a genetic insult in a noncoding region, resulting in diminished expression of the gene product. Reductase deficiency disorder is so common in certain inbred groups that children with ambiguous genitalia are not raised as male or female, but instead are given a third sex assignment in a New Guinea highland tribe (154). -thalassemia/mental retardation syndrome (140). Also, ambiguous genitalia are seen when patients are monosomic for autosomal loci on chromosome 9 (22, 78, 130, 187, 252). It should be noted that one sex-determining autosomal locus on mouse chromosome 4 (108) is syntenic with this region of human chromosome 9, suggesting the two loci may encode homologous gene products. A case report showed that deletion of 10q (446) was associated with an intersex phenotype that included cryptorchidism, micropenis, and hypospadias. In addition, there are several reports of autosomal recessive inheritance of gonadal agenesis (82, 85, 284, 356) or gonadal dysgenesis (218, 312, 349). Cases of agonadism lack the virilization and complete or partial involution of the Müllerian system seen with gonadal dysgenesis, which results from active testicular tissue before degeneration and disappearance. In some cases, gonadal dysgenesis is associated with additional congenital malformations including midline defects (226, 337a). A few reports describe families with inheritance consistent with an X-linked form of partial gonadal dysgenesis (see Ref. 114 for review); because the gonadal phenotypes seen in these families are largely disparate, it is possible that more than one X-linked locus could be responsible for this group of patients.
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FIG. 8.
Summary of gene expression in urogenital ridge. Data are taken from the following sources: 1, Hacker and Lovell-Badge (162); 2, Ikeda et al. (199); 3, Armstrong et al. (10); 4, Bitgood and McMahon (31); 5, Phelps and Dressler (330); 6, Izpisua-Belmonte et al. (203); 7, Matsui et al. (267); 8, Fickenscher et al. (118); 9, Dolle et al. (91); 10, Gaunt et al. (135a). S, Sertoli or Sertoli precursor cells; G, germ cells; L, Leydig cells; GC, granulosa cells; M, peritubular myoid cells; A, all cell types; F, fibroblasts or connective tissue; ME, mesonephric cells or Wolffian duct; CE, celomic epithelium; SO, somatic gonadal cells; EPI, epididymis; OV, ovary; U, unknown cell type(s).
IX. TISSUE-SPECIFIC MARKERS OF TESTICULAR DIFFERENTIATION
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X. CONCLUSIONS
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ACKNOWLEDGEMENTS |
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We thank E. Ukiyama, A. Jancso, N. Morikawa, T. Clarke, G. Chan, J. Radeck, L. Labeots, M. Mellody, M. A. Weiss, and M. Alexander-Bridges for communication of results before publication and M. Weiss, B. Capel, R. Maas, and members of our laboratory for critically reading and discussing the manuscript. We are grateful to S. Fitzpatrick and J. Richards for kindly providing the aromatase reporter, P. Sharp for the HMG 2 expression vector, C. Basilico for the Sox 2 expression vector, M. Alexander-Bridges for the IreABP expression vector, and H. Clevers for the LEF-1 expression vector used in Figure 5.
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FOOTNOTES |
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C. Haqq was supported in part by an award from the Massachusetts General Hospital Fund for Medical Discovery. P. K. Donahoe is supported by National Institute of Child Health and Human Development Grant HD-30812 and the P30 Endocrine Sciences Center at the Massachusetts General Hospital.
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