The decision of the bi-potential gonad to develop into either a testis or ovary is determined by the presence or absence of the Sex-determining Region gene on the Y chromosome (SRY). Since its discovery, almost 13 years ago, the molecular role that SRY plays in initiating the male sexual development cascade has proven difficult to ascertain. While biochemical studies of clinical mutants and mouse genetic models have helped in our understanding of SRY function, no direct downstream targets of SRY have yet been identified. There are, however, a number of other genes of equal importance in determining sexual phenotype, expressed before and after expression of SRY. Of these, one has proven of central importance to mammals and vertebrates, SOX9. This review describes our current knowledge of SRY and SOX9 structure and function in the light of recent key developments.   

1.
Achermann JC, Ito M, Hindmarsh PC, Jameson JL: A mutation in the gene encoding steroidogenic factor-1 causes XY sex reversal and adrenal failure in humans. Nature Genet 22:125–126 (1999).
2.
Achermann JC, Ozisik G, Ito M, Orun UA, Harmanci K, et al: Gonadal determination and adrenal development are regulated by the orphan nuclear receptor steroidogenic factor-1, in a dose-dependent manner. J Clin Endocrinol Metab 87:1829–1833 (2002).
3.
Adams IR, McLaren A: Sexually dimorphic development of mouse primordial germ cells: switching from oogenesis to spermatogenesis. Development 129:1155–1164 (2002).
4.
Affara NA, Chalmers IJ, Ferguson-Smith MA: Analysis of the SRY gene in 22 sex-reversed XY females identifies four new point mutations in the conserved DNA binding domain. Hum molec Genet 2:785–789 (1993).
5.
Albrecht KH, Capel B, Washburn LL, Eicher EM: Defective mesonephric cell migration is associated with abnormal testis cord development in C57BL/6J XY (Mus domesticus) mice. Dev Biol 225:26–36 (2000).
6.
Albrecht KH, Eicher EM: Evidence that Sry is expressed in pre-Sertoli cells and Sertoli and granulosa cells have a common precursor. Dev Biol 240:92–107 (2001).
7.
Albrecht KH, Young M, Washburn LL, Eicher EM: Sry expression level and protein isoform differences play a role in abnormal testis development in C57BL/6J mice carrying certain Sry alleles. Genetics 164:277–288 (2003).
8.
Ang SL, Rossant J: HNF-3 beta is essential for node and notochord formation in mouse development. Cell 78:561–574 (1994).
9.
Anttonen M, Ketola I, Parviainen H, Pusa AK, Heikinheimo M: FOG-2 and GATA4 are coexpressed in the mouse ovary and can modulate mullerian-inhibiting substance expression. Biol Reprod 68:1333–1340 (2003).
10.
Arango NA, Lovell-Badge R, Behringer RR: Targeted mutagenesis of the endogenous mouse Mis gene promoter: in vivo definition of genetic pathways of vertebrate sexual development. Cell 99:409–419 (1999).
11.
Assumpção JG, Guerra AT, Palandi de Mello M: Recurrence of a nonsense mutation in the conserved domain of SRY in a Brazilian patient with 46,XY gonadal dysgenesis. J Pediatr Endocrinol Metab 12:455–457 (1999).
12.
Assumpção JG, Benedetti CE, Maciel-Guerra AT, Guerra Jr G, Baptista MT, et al: Novel mutations affecting SRY DNA-binding activity: the HMG box N65H associated with 46,XY pure gonadal dysgenesis and the familial non-HMG box R30I associated with variable phenotypes. J molec Med 80:782–790 (2002).
13.
Bagheri-Fam S, Ferraz C, Demaille J, Scherer G, Pfeifer D: Comparative genomics of the SOX9 region in human and Fugu rubripes: conservation of short regulatory sequence elements within large intergenic regions. Genomics 78:73–82 (2001).
14.
Barbosa AS, Ferraz-Costa TE, Semer M, Liberman B, Moreira-Filho CA: XY gonadal dysgenesis and gonadoblastoma: a study in two sisters with a cryptic deletion of the Y chromosome involving the SRY gene. Hum Genet 95:63–66 (1995).
15.
Battiloro E, Angeletti B, Tozzi MC, Bruni L, Tondini S, et al: A novel double nucleotide substitution in the HMG box of the SRY gene associated with Swyer syndrome. Hum Genet 100:585–587 (1997).
16.
Baud S, Margeat E, Lumbroso S, Paris F, Sultan C, et al: Equilibrium binding assays reveal the elevated stoichiometry and salt dependence of the interaction between full-length human sex-determining region on the Y chromosome (SRY) and DNA. J biol Chem 277:18404–18410 (2002).
17.
Behringer RR: The in vivo roles of mullerian-inhibiting substance. Curr Top Dev Biol 29:171–187 (1994).
18.
Bergstrom DE, Young M, Albrecht KH, Eicher EM: Related function of mouse SOX3, SOX9, and SRY HMG domains assayed by male sex determination. Genesis 28:111–124 (2000).
19.
Berkovitz GD, Fechner PY, Marcantonio SM, Bland G, Stetten G, et al: The role of the sex-determining region of the Y chromosome (SRY) in the etiology of 46,XX true hermaphroditism. Hum Genet 88:411–416 (1992).
20.
Bernard P, Tang P, Liu S, Dewing P, Harley V, et al: Dimerization of SOX9 is required for chondrogenesis, but not for sex determination. Hum molec Genet 12:1–11 (2003).
21.
Berta P, Hawkins JR, Sinclair AH, Taylor A, Griffiths BL, et al: Genetic evidence equating SRY and the testis-determining factor. Nature 348:448–450 (1990).
22.
Betsholtz C, Karlsson L, Lindahl P: Developmental roles of platelet-derived growth factors. Bioessays 23:494–507 (2001).
23.
Bilbao JR, Loridan L, Castano L: A novel postzygotic nonsense mutation in SRY in familial XY gonadal dysgenesis. Hum Genet 97:537–539 (1996).
24.
Bishop CE, Whitworth DJ, Qin Y, Agoulnik AI, Agoulnik IU, et al: A transgenic insertion upstream of sox9 is associated with dominant XX sex reversal in the mouse. Nature Genet 26:490–494 (2000).
25.
Boucekkine C, Toublanc JE, Abbas N, Chaabouni S, Ouahid S, et al: Clinical and anatomical spectrum in XX sex reversed patients. Relationship to the presence of Y specific DNA-sequences. Clin Endocrinol (Oxf) 40:733–742 (1994).
26.
Bowles J, Cooper L, Berkman J, Koopman P: Sry requires a CAG repeat domain for male sex determination in Mus musculus. Nature Genet 22:405–408 (1999).
27.
Braun A, Kammerer S, Cleve H, Lohrs U, Schwarz HP, et al: True hermaphroditism in a 46,XY individual, caused by a postzygotic somatic point mutation in the male gonadal sex-determining locus (SRY): molecular genetics and histological findings in a sporadic case. Am J hum Genet 52:578–585 (1993).
28.
Brennan J, Karl J, Capel B: Divergent vascular mechanisms downstream of Sry establish the arterial system in the XY gonad. Dev Biol 244:418–428 (2002).
29.
Brennan J, Tilmann C, Capel B: Pdgfr-alpha mediates testis cord organization and fetal Leydig cell development in the XY gonad. Genes Dev 17:800–810 (2003).
30.
Brown S, Yu C, Lanzano P, Heller D, Thomas L, et al: A de novo mutation (Gln2Stop) at the 5′ end of the SRY gene leads to sex reversal with partial ovarian function. Am J hum Genet 62:189–192 (1998).
31.
Buehr M, Gu S, McLaren A: Mesonephric contribution to testis differentiation in the fetal mouse. Development 117:273–281 (1993).
32.
Bullejos M, Koopman P: Spatially dynamic expression of Sry in mouse genital ridges. Dev Dyn 221:201–205 (2001).
33.
Burgoyne PS, Buehr M, Koopman P, Rossant J, McLaren A: Cell-autonomous action of the testis-determining gene: Sertoli cells are exclusively XY in XX–XY chimaeric mouse testes. Development 102:443–450 (1988).
34.
Cameron FJ, Sinclair AH: Mutations in SRY and SOX9: testis-determining genes. Hum Mutat 9:388–395 (1997).
35.
Cameron FJ, Smith MJ, Warne GL, Sinclair AH: Novel mutation in the SRY gene results in 46,XY gonadal dysgenesis. Hum Mutat Suppl 1:S110–111 (1998).
36.
Canto P, de la Chesnaye E, Lopez M, Cervantes A, Chavez B, et al: A mutation in the 5′ non-high mobility group box region of the SRY gene in patients with Turner syndrome and Y mosaicism. J Clin Endocrinol Metab 85:1908–1911 (2000).
37.
Capel B, Rasberry C, Dyson J, Bishop CE, Simpson E, et al: Deletion of Y chromosome sequences located outside the testis determining region can cause XY female sex reversal. Nature Genet 5:301–307 (1993).
38.
Capel B, Albrecht KH, Washburn LL, Eicher EM: Migration of mesonephric cells into the mammalian gonad depends on Sry. Mech Dev 84:127–131 (1999).
39.
Chiang EF, Pai CI, Wyatt M, Yan YL, Postlethwait J, et al: Two sox9 genes on duplicated zebrafish chromosomes: expression of similar transcription activators in distinct sites. Dev Biol 231:149–163 (2001).
40.
Clepet C, Schafer AJ, Sinclair AH, Palmer MS, Lovell-Badge R, et al: The human SRY transcript. Hum molec Genet 2:2007–2012 (1993).
41.
Colvin JS, Green RP, Schmahl J, Capel B, Ornitz DM: Male-to-female sex reversal in mice lacking fibroblast growth factor 9. Cell 104:875–889 (2001).
42.
Coward P, Nagai K, Chen D, Thomas HD, Nagamine CM, et al: Polymorphism of a CAG trinucleotide repeat within Sry correlates with B6.YDom sex reversal. Nature Genet 6:245–250 (1994).
43.
Crawford PA, Dorn C, Sadovsky Y, Milbrandt J: Nuclear receptor DAX-1 recruits nuclear receptor corepressor N-CoR to steroidogenic factor 1. Mol Cell Biol 18:2949–2956 (1998).
44.
Cupp AS, Uzumcu M, Skinner MK: Chemotactic role of neurotropin 3 in the embryonic testis that facilitates male sex determination. Biol Reprod 68:2033–2037 (2003).
45.
Damiani D, Fellous M, McElreavey K, Barbaux S, Barreto ES, et al: True hermaphroditism: clinical aspects and molecular studies in 16 cases. Eur J Endocrinol 136:201–204 (1997).
46.
Daneau I, Pilon N, Boyer A, Behdjani R, Overbeek PA, et al: The porcine SRY promoter is transactivated within a male genital ridge environment. Genesis 33:170–180 (2002).
47.
De Santa Barbara P, Bonneaud N, Boizet B, Desclozeaux M, Moniot B, et al: Direct interaction of SRY-related protein SOX9 and steroidogenic factor 1 regulates transcription of the human anti-Mullerian hormone gene. Mol Cell Biol 18:6653–6665 (1998).
48.
De Santa Barbara P, Moniot B, Poulat F, Berta P: Expression and subcellular localization of SF-1, SOX9, WT1, and AMH proteins during early human testicular development. Dev Dyn 217:293–298 (2000).
49.
De Santa Barbara P, Mejean C, Moniot B, Malcles MH, Berta P, et al: Steroidogenic factor-1 contributes to the cyclic-adenosine monophosphate down-regulation of human SRY gene expression. Biol Reprod 64:775–783 (2001).
50.
De Vries GJ, Rissman EF, Simerly RB, Yang LY, Scordalakes EM, et al: A model system for study of sex chromosome effects on sexually dimorphic neural and behavioral traits. J Neurosci 22:9005–9014 (2002).
51.
Desclozeaux M, Poulat F, de Santa Barbara P, Soullier S, Jay P, et al: Characterization of two Sp1 binding sites of the human sex determining SRY promoter. Biochim biophys Acta 1397:247–252 (1998a).
52.
Desclozeaux M, Poulat F, de Santa Barbara P, Capony JP, Turowski P, et al: Phosphorylation of an N-terminal motif enhances DNA-binding activity of the human SRY protein. J biol Chem 273:7988–7995 (1998b).
53.
Domenice S, Yumie Nishi M, Correia Billerbeck AE, Latronico AC, Aparecida Medeiros M, et al: A novel missense mutation (S18N) in the 5′ non-HMG box region of the SRY gene in a patient with partial gonadal dysgenesis and his normal male relatives. Hum Genet 102:213–215 (1998).
54.
Dörk T, Stuhrmann M, Miller K, Schmidtke J: Independent observation of SRY mutation I90M in a patient with complete gonadal dysgenesis. Hum Mutat 11:90–91 (1998).
55.
Dubin RA, Ostrer H: Sry is a transcriptional activator. Mol Endocrinol 8:1182–1192 (1994).
56.
Dupont S, Dennefeld C, Krust A, Chambon P, Mark M: Expression of Sox9 in granulosa cells lacking the estrogen receptors, ERalpha and ERbeta. Dev Dyn 226:103–106 (2003).
57.
Eicher EM, Washburn LL, Schork NJ, Lee BK, Shown EP, et al: Sex-determining genes on mouse autosomes identified by linkage analysis of C57BL/ 6J-YPOS sex reversal. Nature Genet 14:206–209 (1996).
58.
Fernandez R, Marchal JA, Sanchez A, Pasaro E: A point mutation, R59G, within the HMG-SRY box in a female 45,X/46,X, psu dic(Y)(pter→q11::q11→pter). Hum Genet 111:242–246 (2002).
59.
Forwood JK, Harley V, Jans DA: The C-terminal nuclear localization signal of the SRY HMG domain mediates nuclear import through importin beta1. J biol Chem 276:46575–46582 (2001).
60.
Foster JW, Dominguez-Steglich MA, Guioli S, Kowk G, Weller PA, et al: Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene. Nature 372:525–530 (1994).
61.
Gasca S, Canizares J, De Santa Barbara P, Mejean C, Poulat F, et al: A nuclear export signal within the high mobility group domain regulates the nucleocytoplasmic translocation of SOX9 during sexual determination. Proc natl Acad Sci, USA 99:11199–11204 (2002).
62.
Giese K, Pagel J, Grosschedl R: Distinct DNA-binding properties of the high mobility group domain of murine and human SRY sex-determining factors. Proc natl Acad Sci, USA 91:3368–3372 (1994).
63.
Graves JA: Evolution of the mammalian Y chromosome and sex-determining genes. J exp Zool 281:472–481 (1998).
64.
Graves PE, Davis D, Erickson RP, Lopez M, Kofman-Alfaro S, et al: Ascertainment and mutational studies of SRY in nine XY females. Am J med Genet 83:138–139 (1999).
65.
Grosschedl R, Giese K, Pagel J: HMG domain proteins: architectural elements in the assembly of nucleoprotein structures. Trends Genet 10:94–100 (1994).
66.
Hacker A, Capel B, Goodfellow P, Lovell-Badge R: Expression of Sry, the mouse sex determining gene. Development 121:1603–1614 (1995).
67.
Hadjiathanasiou CG, Brauner R, Lortat-Jacob S, Nivot S, Jaubert F, et al: True hermaphroditism: genetic variants and clinical management. J Pediatr 125:738–744 (1994).
68.
Hageman RM, Cameron FJ, Sinclair AH: Mutation analysis of the SOX9 gene in a patient with campomelic dysplasia. Hum Mutat Suppl 1:S112–113 (1998).
69.
Hanley NA, Hagan DM, Clement-Jones M, Ball SG, Strachan T, et al: SRY, SOX9, and DAX1 expression patterns during human sex determination and gonadal development. Mech Dev 91:403–407 (2000).
70.
Harley VR, Jackson DI, Hextall PJ, Hawkins JR, Berkovitz GD, et al: DNA binding activity of recombinant SRY from normal males and XY females. Science 255:453–456 (1992).
71.
Harley VR, Lovell-Badge R, Goodfellow PN: Definition of a consensus DNA binding site for SRY. Nucl Acids Res 22:1500–1501 (1994).
72.
Harley VR, Lovell-Badge R, Goodfellow PN, Hextall PJ: The HMG box of SRY is a calmodulin binding domain. FEBS Lett 391:24–28 (1996).
73.
Harley VR, Layfield S, Mitchell CL, Forwood JK, John AP, et al: Defective importin (beta) recognition and nuclear import of the sex-determining factor SRY are associated with XY sex-reversing mutations. Proc natl Acad Sci, USA 100:7045–7050 (2003).
74.
Harry JL, Koopman P, Brennan FE, Graves JA, Renfree MB: Widespread expression of the testis-determining gene SRY in a marsupial. Nature Genet 11:347–349 (1995).
75.
Hawkins JR, Taylor A, Berta P, Levilliers J, Van der Auwera B, et al: Mutational analysis of SRY: nonsense and missense mutations in XY sex reversal. Hum Genet 88:471–474 (1992).
76.
Hawkins JR, Taylor A, Goodfellow PN, Migeon CJ, Smith KD, et al: Evidence for increased prevalence of SRY mutations in XY females with complete rather than partial gonadal dysgenesis. Am J hum Genet 51:979–984 (1992).
77.
Hines RS, Tho SP, Zhang YY, Plouffe L, Jr, Hansen KA, et al: Paternal somatic and germ-line mosaicism for a sex-determining region on Y (SRY) missense mutation leading to recurrent 46,XY sex reversal. Fertil Steril 67:675–679 (1997).
78.
Hiort O, Gramss B, Klauber GT: True hermaphroditism with 46,XY karyotype and a point mutation in the SRY gene. J Pediatr 126:1022 (1995).
79.
Hossain A, Saunders GF: The human sex-determining gene SRY is a direct target of WT1. J biol Chem 276:16817–16823 (2001).
80.
Houston CS, Opitz JM, Spranger JW, Macpherson RI, Reed MH, et al: The campomelic syndrome: review, report of 17 cases, and follow-up on the currently 17-year-old boy first reported by Maroteaux et al in 1971. Am J med Genet 15:3–28 (1983).
81.
Huang B, Wang S, Ning Y, Lamb AN, Bartley J: Autosomal XX sex reversal caused by duplication of SOX9. Am J med Genet 87:349–353 (1999).
82.
Huang W, Zhou X, Lefebvre V, de Crombrugghe B: Phosphorylation of SOX9 by cyclic AMP-dependent protein kinase A enhances SOX9’s ability to transactivate a Col2a1 chondrocyte-specific enhancer. Mol Cell Biol 20:4149–4158 (2000).
83.
Iida T, Nakahori Y, Komaki R, Mori E, Hayashi N, et al: A novel nonsense mutation in the HMG box of the SRY gene in a patient with XY sex reversal. Hum molec Genet 3:1437–1438 (1994).
84.
Imai A, Takagi A, Tamaya T: A novel sex-determining region on Y (SRY) missense mutation identified in a 46,XY female and also in the father. Endocr J 46:735–739 (1999).
85.
Inoue H, Nomura M, Yanase T, Ichino I, Goto K, et al: A rare case of 46,XX true hermaphroditism with hidden mosaicism with sex-determining region Y chromosome-bearing cells in the gonads. Intern Med 37:467–471 (1998).
86.
Ito M, Yu R, Jameson JL: DAX-1 inhibits SF-1-mediated transactivation via a carboxy-terminal domain that is deleted in adrenal hypoplasia congenita. Mol Cell Biol 17:1476–1483 (1997).
87.
Jäger RJ, Anvret M, Hall K, Scherer G: A human XY female with a frame shift mutation in the candidate testis-determining gene SRY. Nature 348:452–454 (1990).
88.
Jäger RJ, Harley VR, Pfeiffer RA, Goodfellow PN, Scherer G: A familial mutation in the testis-determining gene SRY shared by both sexes. Hum Genet 90:350–355 (1992).
89.
Jakubiczka S, Bettecken T, Stumm M, Neulen J, Wieacker P: Another mutation within the HMG-box of the SRY gene associated with Swyer syndrome. Hum Mutat 13:85 (1998).
90.
Jamieson RV, Zhou SX, Wheatley SC, Koopman P, Tam PP: Sertoli cell differentiation and Y-chromosome activity: a developmental study of X-linked transgene activity in sex-reversed X/XSxra mouse embryos. Dev Biol 199:235–44 (1998).
91.
Jordan BK, Jain M, Natarajan S, Frasier SD, Vilain E: Familial mutation in the testis-determining gene SRY shared by an XY female and her normal father. J Clin Endocrinol Metab 87:3428–3432 (2002).
92.
Just W, Rau W, Vogel W, Akhverdian M, Fredga K, et al: Absence of Sry in species of the vole Ellobius. Nature Genet 11:117–118 (1995).
93.
Kanai Y, Koopman P: Structural and functional characterization of the mouse Sox9 promoter: implications for campomelic dysplasia. Hum molec Genet 8:691–696 (1999).
94.
Karl J, Capel B: Sertoli cells of the mouse testis originate from the coelomic epithelium. Dev Biol 203:323–333 (1998).
95.
Koopman P: Sry and Sox9: mammalian testis-determining genes. Cell Mol Life Sci 55:839–856 (1999).
96.
Koopman P, Munsterberg A, Capel B, Vivian N, Lovell-Badge R: Expression of a candidate sex-determining gene during mouse testis differentiation. Nature 348:450–452 (1990).
97.
Koopman P, Gubbay J, Vivian N, Goodfellow P, Lovell-Badge R: Male development of chromosomally female mice transgenic for Sry. Nature 351:117–1121 (1991).
98.
Koopman P, Bullejos M, Bowles J: Regulation of male sexual development by Sry and Sox9. J exp Zool 290:463–474 (2001).
99.
Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, et al: WT-1 is required for early kidney development. Cell 74:679–691 (1993).
100.
Kwok C, Weller PA, Guioli S, Foster JW, Mansour S, et al: Mutations in SOX9, the gene responsible for Campomelic dysplasia and autosomal sex reversal. Am J hum Genet 57:1028–1036 (1995).
101.
Kwok C, Tyler-Smith C, Mendonca BB, Hughes I, Berkovitz GD, et al: Mutation analysis of the 2 kb 5′ to SRY in XY females and XY intersex subjects. J med Genet 33:465–468 (1996a).
102.
Kwok C, Goodfellow PN, Hawkins JR: Evidence to exclude SOX9 as a candidate gene for XY sex reversal without skeletal malformation. J med Genet 33:800–801 (1996b).
103.
Lee CH, Taketo T: Low levels of Sry transcripts cannot be the sole cause of B6-Y(TIR) sex reversal. Genesis 30:7–11 (2001).
104.
Lee YS, Chuong CM: Activation of protein kinase A is a pivotal step involved in both BMP-2- and cyclic AMP-induced chondrogenesis. J Cell Physiol 170:153–165 (1997).
105.
Li B, Zhang W, Chan G, Jancso-Radek A, Liu S, et al: Human sex reversal due to impaired nuclear localization of SRY: a clinical correlation. J biol Chem 276:46480–46484 (2001).
106.
Lovell-Badge R, Canning C, Sekido R: Sex-determining genes in mice: building pathways. Novartis Found Symp 244:4-18; discussion 18–22, 35–42, 253–257 (2002).
107.
Lu MF, Cheng HT, Kern MJ, Potter SS, Tran B, et al: prx-1 functions cooperatively with another paired-related homeobox gene, prx-2, to maintain cell fates within the craniofacial mesenchyme. Development 126:495–504 (1999).
108.
Lundberg Y, Ritzen A, Harlin J, Wedell A: Novel missense mutation (P131R) in the HMG box of SRY in XY sex reversal. Hum Mutat Suppl 1:S328 (1998).
109.
Luo X, Ikeda Y, Parker KL: A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation. Cell 77:481–490 (1994).
110.
Maheswaran S, Englert C, Zheng G, Lee SB, Wong J, et al: Inhibition of cellular proliferation by the Wilms tumor suppressor WT1 requires association with the inducible chaperone Hsp70. Genes Dev 12:1108–1120 (1998).
111.
Mansour S, Hall CM, Pembrey ME, Young ID: A clinical and genetic study of campomelic dysplasia. J Med Genet 32:415–420 (1995).
112.
Margarit E, Guillen A, Rebordosa C, Vidal-Taboada J, Sanchez M, et al: Identification of conserved potentially regulatory sequences of the SRY gene from 10 different species of mammals. Biochem biophys Res Commun 245:370–377 (1998).
113.
Marshall OJ, Harley VR: Identification of an interaction between SOX9 and HSP70. FEBS Lett 496:75–80 (2001).
114.
Martin JF, Bradley A, Olson EN: The paired-like homeo box gene MHox is required for early events of skeletogenesis in multiple lineages. Genes Dev 9:1237–1249 (1995).
115.
Martineau J, Nordqvist K, Tilmann C, Lovell-Badge R, Capel B: Male-specific cell migration into the developing gonad. Curr Biol 7:958–968 (1997).
116.
Mayer A, Mosler G, Just W, Pilgrim C, Reisert I: Developmental profile of Sry transcripts in mouse brain. Neurogenetics 3:25–30 (2000).
117.
McDowall S, Argentaro A, Ranganathan S, Weller P, Mertin S, et al: Functional and structural studies of wild type SOX9 and mutations causing campomelic dysplasia. J biol Chem 274:24023–24030 (1999).
118.
McElreavey K, Fellous M: Sex determination and the Y chromosome. Am J med Genet 89:176–185 (1999).
119.
McElreavey K, Vilain E, Abbas N, Costa JM, Souleyreau N, et al: XY sex reversal associated with a deletion 5′ to the SRY “HMG box” in the testis-determining region. Proc natl Acad Sci, USA 89:11016–11020 (1992a).
120.
McElreavey K, Rappaport R, Vilain E, Abbas N, Richaud F, et al: A minority of 46,XX true hermaphrodites are positive for the Y-DNA sequence including SRY. Hum Genet 90:121–125 (1992b).
121.
McElreavey KD, Vilain E, Boucekkine C, Vidaud M, Jaubert F, et al: XY sex reversal associated with a nonsense mutation in SRY. Genomics 13:838–840 (1992c).
122.
McElreavey K, Vilain E, Abbas N, Herskowitz I, Fellous M: A regulatory cascade hypothesis for mammalian sex determination: SRY represses a negative regulator of male development. Proc natl Acad Sci, USA 90:3368–3372 (1993).
123.
McElreavey K, Vilain E, Barbaux S, Fuqua JS, Fechner PY, et al: Loss of sequences 3′ to the testis-determining gene, SRY, including the Y pseudoautosomal boundary associated with partial testicular determination. Proc natl Acad Sci, USA 93:8590–8594 (1996).
124.
Merchant-Larios H, Moreno-Mendoza N, Buehr M: The role of the mesonephros in cell differentiation and morphogenesis of the mouse fetal testis. Int J Dev Biol 37:407–415 (1993).
125.
Mertin S, McDowall SG, Harley VR: The DNA-binding specificity of SOX9 and other SOX proteins. Nucl Acids Res 27:1359–1364 (1999).
126.
Meyer J, Sudbeck P, Held M, Wagner T, Schmitz ML, et al: Mutational analysis of the SOX9 gene in campomelic dysplasia and autosomal sex reversal: lack of genotype/phenotype correlations. Hum molec Genet 6:91–98 (1997).
127.
Mitchell CL, Harley VR: Biochemical defects in eight SRY missense mutations causing XY gonadal dysgenesis. Mol Genet Metab 77:217–225 (2002).
128.
Modan-Moses D, Litmanovitch T, Rienstein S, Meyerovitch J, Goldman B, et al: True hermaphroditism with ambiguous genitalia due to a complicated mosaic karyotype: clinical features, cytogenetic findings, and literature review. Am J med Genet 116A:300–303 (2003).
129.
Morais da Silva S, Hacker A, Harley V, Goodfellow P, Swain A, et al: Sox9 expression during gonadal development implies a conserved role for the gene in testis differentiation in mammals and birds. Nature Genet 14:62–68 (1996).
130.
Moreno-Mendoza N, Harley VR, Merchant-Larios H: Differential expression of SOX9 in gonads of the sea turtle Lepidochelys olivacea at male- or female-promoting temperatures. J exp Zool 284:705–710 (1999).
131.
Muller J, Schwartz M, Skakkebaek NE: Analysis of the sex-determining region of the Y chromosome (SRY) in sex reversed patients: point-mutation in SRY causing sex-reversion in a 46,XY female. J Clin Endocrinol Metab 75:331–333 (1992).
132.
Murakami S, Lefebvre V, de Crombrugghe B: Potent inhibition of the master chondrogenic factor Sox9 gene by interleukin-1 and tumor necrosis factor-alpha. J biol Chem 275:3687–3692 (2000).
133.
Nachtigal MW, Hirokawa Y, Enyeart-VanHouten DL, Flanagan JN, Hammer GD, et al: Wilms’ tumor 1 and Dax-1 modulate the orphan nuclear receptor SF-1 in sex-specific gene expression. Cell 93:445–454 (1998).
134.
Nagamine CM: The testis-determining gene, SRY, exists in multiple copies in Old World rodents. Genet Res 64:151–159 (1994).
135.
Ng KW, Ridgway P, Cohen DR, Tremethick DJ: The binding of a Fos/Jun heterodimer can completely disrupt the structure of a nucleosome. EMBO J 16:2072–2085 (1997).
136.
Ng LJ, Wheatley S, Muscat GE, Conway-Campbell J, Bowles J, et al: SOX9 binds DNA, activates transcription, and coexpresses with type II collagen during chondrogenesis in the mouse. Dev Biol 183:108–121 (1997).
137.
van Niekerk WA, Retief AE: The gonads of human true hermaphrodites. Hum Genet 58:117–122 (1981).
138.
Okuhara K, Tajima T, Nakae J, Fujieda K: A novel missense mutation in the HMG box region of the SRY gene in a Japanese patient with an XY sex reversal. J hum Genet 45:112–114 (2000).
139.
Oreal E, Pieau C, Mattei MG, Josso N, Picard JY, et al: Early expression of AMH in chicken embryonic gonads precedes testicular SOX9 expression. Dev Dyn 212:522–532 (1998).
140.
Ortenberg J, Oddoux C, Craver R, McElreavey K, Salas-Cortes L, et al: SRY gene expression in the ovotestes of XX true hermaphrodites. J Urol 167:1828–1831 (2002).
141.
Ostrer H: Sex determination: lessons from families and embryos. Clin Genet 59:207–215 (2001).
142.
Palmer SJ, Burgoyne PS: XY follicle cells in the ovaries of XO/XY and XO/XY/XYY mosaic mice. Development 111:1017–1019 (1991).
143.
Parker KL: The roles of steroidogenic factor 1 in endocrine development and function. Mol Cell Endocrinol 140:59–63 (1998).
144.
Parma P, Pailhoux E, Cotinot C: Reverse transcription-polymerase chain reaction analysis of genes involved in gonadal differentiation in pigs. Biol Reprod 61:741–748 (1999).
145.
Patek CE, Kerr JB, Gosden RG, Jones KW, Hardy K, et al: Sex chimaerism, fertility and sex determination in the mouse. Development 113:311–325 (1991).
146.
Patek CE, Little MH, Fleming S, Miles C, Charlieu JP, et al: A zinc finger truncation of murine WT1 results in the characteristic urogenital abnormalities of Denys-Drash syndrome. Proc natl Acad Sci, USA 96:2931–2936 (1999).
147.
Payen E, Pailhoux E, Abou Merhi R, Gianquinto L, Kirszenbaum M, et al: Characterization of ovine SRY transcript and developmental expression of genes involved in sexual differentiation. Int J Dev Biol 40:567–575 (1996).
148.
Perkins ND, Edwards NL, Duckett CS, Agranoff AB, Schmid RM, et al: A cooperative interaction between NF-kappa B and Sp1 is required for HIV-1 enhancer activation. EMBO J 12:3551–3558 (1993).
149.
Pfeifer D, Kist R, Dewar K, Devon K, Lander ES, et al: Campomelic dysplasia translocation breakpoints are scattered over 1 Mb proximal to SOX9: evidence for an extended control region. Am J hum Genet 65:111–124 (1999).
150.
Pilon N, Daneau I, Paradis V, Hamel F, Lussier JG, et al: Porcine SRY Promoter Is a Target for Steroidogenic Factor 1. Biol Reprod 68:1098–1106 (2003).
151.
Pontiggia A, Rimini R, Harley VR, Goodfellow PN, Lovell-Badge R, et al: Sex-reversing mutations affect the architecture of SRY-DNA complexes. EMBO J 13:6115–6124 (1994).
152.
Poulat F, Soullier S, Goze C, Heitz F, Calas B, et al: Description and functional implications of a novel mutation in the sex-determining gene SRY. Hum Mutat 3:200–204 (1994).
153.
Poulat F, Girard F, Chevron MP, Goze C, Rebillard X, et al: Nuclear localization of the testis determining gene product SRY. J Cell Biol 128:737–748 (1995).
154.
Poulat F, Barbara PS, Desclozeaux M, Soullier S, Moniot B, et al: The human testis determining factor SRY binds a nuclear factor containing PDZ protein interaction domains. J biol Chem 272:7167–7172 (1997).
155.
Preiss S, Argentaro A, Clayton A, John A, Jans DA, et al: Compound effects of point mutations causing campomelic dysplasia/autosomal sex reversal upon SOX9 structure, nuclear transport, DNA binding, and transcriptional activation. J biol Chem 276:27864–27872 (2001).
156.
Queipo G, Zenteno JC, Pena R, Nieto K, Radillo A, et al: Molecular analysis in true hermaphroditism: demonstration of low-level hidden mosaicism for Y-derived sequences in 46,XX cases. Hum Genet 111:278–283 (2002).
157.
Rossi P, Dolci S, Albanesi C, Grimaldi P, Geremia R: Direct evidence that the mouse sex-determining gene Sry is expressed in the somatic cells of male fetal gonads and in the germ cell line in the adult testis. Mol Reprod Dev 34:369–373 (1993).
158.
Schaefer JF, Millham ML, de Crombrugghe B, Buckbinder L: FGF signaling antagonizes cytokine-mediated repression of Sox9 in SW1353 chondrosarcoma cells. Osteoarthritis Cartilage 11:233–241 (2003).
159.
Schaffler A, Barth N, Winkler K, Zietz B, Rummele P, et al: Identification of a new missense mutation (Gly95Glu) in a highly conserved codon within the high-mobility group box of the sex-determining region Y gene: report on a 46,XY female with gonadal dysgenesis and yolk-sac tumor. J Clin Endocrinol Metab 85:2287–2292 (2000).
160.
Schepers G, Wilson M, Wilhelm D, Koopman P: SOX8 is expressed during testis differentiation in mice and synergises with SF1 to activate the Amh promoter in vitro. J biol Chem 278:28101–28108 (2003).
161.
Scherer G: The molecular genetic jigsaw puzzle of vertebrate sex determination and its missing pieces. Novartis Found Symp 244:225–236; discussion 236–239, 253–257 (2002).
162.
Scherer G, Held M, Erdel M, Meschede D, Horst J, et al: Three novel SRY mutations in XY gonadal dysgenesis and the enigma of XY gonadal dysgenesis cases without SRY mutations. Cytogenet Cell Genet 80:188–192 (1998).
163.
Schmahl J, Eicher EM, Washburn LL, Capel B: Sry induces cell proliferation in the mouse gonad. Development 127:65–73 (2000).
164.
Schmitt-Ney M, Thiele H, Kaltwasser P, Bardoni B, Cisternino M, et al: Two novel SRY missense mutations reducing DNA binding identified in XY females and their mosaic fathers. Am J hum Genet 56:862–869 (1995).
165.
Sekiya I, Koopman P, Tsuji K, Mertin S, Harley V, et al: Dexamethasone enhances SOX9 expression in chondrocytes. J Endocrinol 169:573–579 (2001).
166.
Shen JH, Ingraham HA: Regulation of the orphan nuclear receptor steroidogenic factor 1 by Sox proteins. Mol Endocrinol 16:529–540 (2002).
167.
Shen WH, Moore CC, Ikeda Y, Parker KL, Ingraham HA: Nuclear receptor steroidogenic factor 1 regulates the mullerian inhibiting substance gene: a link to the sex determination cascade. Cell 77:651–661 (1994).
168.
Shimamura R, Fraizer GC, Trapman J, Lau YFC, Saunders GF: The Wilms’ tumor gene WT1 can regulate genes involved in sex determination and differentiation: SRY, Mullerian-inhibiting substance, and the androgen receptor. Clin Cancer Res 3:2571–2580 (1997).
169.
Sinclair AH, Berta P, Palmer MS, Hawkins JR, Griffiths BL, et al: A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif. Nature 346:240–244 (1990).
170.
Su H, Lau YF: Identification of the transcriptional unit, structural organization, and promoter sequence of the human sex-determining region Y (SRY) gene, using a reverse genetic approach. Am J hum Genet 52:24–38 (1993).
171.
Sudbeck P, Schmitz ML, Baeuerle PA, Scherer G: Sex reversal by loss of the C-terminal transactivation domain of human SOX9. Nature Genet 13:230–232 (1996).
172.
Sudbeck P, Scherer G: Two independent nuclear localization signals are present in the DNA-binding high-mobility group domains of SRY and SOX9. J biol Chem 272:27848–27852 (1997).
173.
Swain A, Narvaez V, Burgoyne P, Camerino G, Lovell-Badge R: Dax1 antagonizes Sry action in mammalian sex determination. Nature 391:761–767 (1998).
174.
Sweitzer TD, Hanover JA: Calmodulin activates nuclear protein import: a link between signal transduction and nuclear transport. Proc natl Acad Sci, USA 93:14574–14579 (1996).
175.
Tajima T, Nakae J, Shinohara N, Fujieda K: A novel mutation localized in the 3′ non-HMG box region of the SRY gene in 46,XY gonadal dysgenesis. Hum molec Genet 3:1187–1189 (1994).
176.
Takagi A, Imai A, Tamaya T: A novel sex-determining region on Y (SRY) nonsense mutation identified in a 45,X/47,XYY female. Fertil Steril 72:167–169 (1999).
177.
Takamatsu N, Kanda H, Ito M, Yamashita A, Yamashita S, et al: Rainbow trout SOX9: cDNA cloning, gene structure and expression. Gene 202:167–170 (1997).
178.
Tevosian SG, Albrecht KH, Crispino JD, Fujiwara Y, Eicher EM, et al: Gonadal differentiation, sex determination and normal Sry expression in mice require direct interaction between transcription partners GATA4 and FOG2. Development 129:4627–4634 (2002).
179.
Tilmann C, Capel B: Mesonephric cell migration induces testis cord formation and Sertoli cell differentiation in the mammalian gonad. Development 126:2883–2890 (1999).
180.
Tilmann C, Capel B: Cellular and molecular pathways regulating mammalian sex determination. Recent Prog Horm Res 57:1–18 (2002).
181.
Torres L, Lopez M, Mendez JP, Canto P, Cervantes A, et al: Molecular analysis in true hermaphrodites with different karyotypes and similar phenotypes. Am J med Genet 63:348–355 (1996).
182.
Tremblay JJ, Viger RS: GATA factors differentially activate multiple gonadal promoters through conserved GATA regulatory elements. Endocrinology 142:977–986 (2001).
183.
Uehara S, Funato T, Yaegashi N, Suziki H, Sato J, et al: SRY mutation and tumor formation on the gonads of XP pure gonadal dysgenesis patients. Cancer Genet Cytogenet 113:78–84 (1999).
184.
Uusitalo H, Hiltunen A, Ahonen M, Gao TJ, Lefebvre V, et al: Accelerated up-regulation of L-Sox5, Sox6, and Sox9 by BMP-2 gene transfer during murine fracture healing. J Bone Miner Res 16:1837–1845 (2001).
185.
Veitia R, Ion A, Barbaux S, Jobling MA, Souleyreau N, et al: Mutations and sequence variants in the testis-determining region of the Y chromosome in individuals with a 46,XY female phenotype. Hum Genet 99:648–652 (1997).
186.
Vidal VP, Chaboissier MC, de Rooij DG, Schedl A: Sox9 induces testis development in XX transgenic mice. Nature Genet 28:216–217 (2001).
187.
Viger RS, Mertineit C, Trasler JM, Nemer M: Transcription factor GATA4 is expressed in a sexually dimorphic pattern during mouse gonadal development and is a potent activator of the Mullerian inhibiting substance promoter. Development 125:2665–2675 (1998).
188.
Vilain E, McCabe ER: Mammalian sex determination: from gonads to brain. Mol Genet Metab 65:74–84 (1998).
189.
Wagner T, Wirth J, Meyer J, Zabel B, Held M, et al: Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9. Cell 79:1111–1120 (1994).
190.
Watanabe K, Clarke TR, Lane AH, Wang X, Donahoe PK: Endogenous expression of Mullerian inhibiting substance in early postnatal rat sertoli cells requires multiple steroidogenic factor-1 and GATA4-binding sites. Proc natl Acad Sci, USA 97:1624–1629 (2000).
191.
Western PS, Harry JL, Graves JA, Sinclair AH: Temperature-dependent sex determination: upregulation of SOX9 expression after commitment to male development. Dev Dyn 214:171–177 (1999).
192.
Whitfield LS, Lovell-Badge R, Goodfellow PN: Rapid sequence evolution of the mammalian sex-determining gene SRY. Nature 364:713–715 (1993).
193.
Wirth J, Wagner T, Meyer J, Pfeiffer RA, Tietze HU, et al: Translocation breakpoints in three patients with campomelic dysplasia and autosomal sex reversal map more than 130 kb from SOX9. Hum Genet 97:186–193 (1996).
194.
Wunderle VM, Critcher R, Hastie N, Goodfellow PN, Schedl A: Deletion of long-range regulatory elements upstream of SOX9 causes campomelic dysplasia. Proc natl Acad Sci, USA 95:10649–10654 (1998).
195.
Yokouchi K, Ito M, Nishino K, Yamanouchi K, Naito K, et al: Stage-specific regulatory element of mouse Sry gene. Mol Reprod Dev 64:389–396 (2003).
196.
Zazopoulos E, Lalli E, Stocco DM, Sassone-Corsi P: DNA binding and transcriptional repression by DAX-1 blocks steroidogenesis. Nature 390:311–315 (1997).
197.
Zehentner BK, Leser U, Burtscher H: BMP-2 and sonic hedgehog have contrary effects on adipocyte-like differentiation of C3H10T1/2 cells. DNA Cell Biol 19:275–281 (2000).
198.
Zeng YT, Ren ZR, Zhang ML, Huang Y, Zeng FY, et al: A new de novo mutation (A113T) in HMG box of the SRY gene leads to XY gonadal dysgenesis. J med Genet 30:655–657 (1993).
199.
Zhang J, Coward P, Xian M, Lau YF: In vitro binding and expression studies demonstrate a role for the mouse Sry Q-rich domain in sex determination. Int J Dev Biol 43:219–227 (1999).
200.
Zhao LJ, Zhang S, Chinnadurai G: Sox9 transactivation and testicular expression of a novel human gene, KIAA0800. J Cell Biochem 86:277–289 (2002).
201.
Zhi L, Zheng-Gang X, Guanghui X: Molecular analysis of SRY gene of seven 46, XY females. Chin Med J Genet 12:258–261 (1996).
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