Mammalian sex determination—insights from humans and mice

Achermann JC, Ito M, Hindmarsh PC, Jameson JL (1999) A mutation in the gene encoding steroidogenic factor-1 causes XY sex reversal and adrenal failure in humans. Nat Genet 22:125–126 Aleck KA, Argueso L, Stone J, Hackel JG, Erickson RP (1999) True hermaphroditism with partial duplication of chromosome 22 and without SRY. Am J Med Genet 85:2–4 Andrieux J, Dubourg C, Rio M et al (2009) Genotype–phenotype correlation in four 15q24 deleted patients identified by array-CGH. Am J Med Genet A 149A:2813–2819 Arango NA, Lovell-Badge R, Behringer RR (1999) Targeted mutagenesis of the endogenous mouse Mis gene promoter: in vivo definition of genetic pathways of vertebrate sexual development. Cell 99:409–419 Armstrong JF, Pritchard-Jones K, Bickmore WA, Hastie ND, Bard JB (1993) The expression of the Wilms' tumour gene, WT1, in the developing mammalian embryo. Mech Dev 40:85–97 Audi L, Fernandez-Cancio M, Carrascosa A et al (2010) Novel (60%) and recurrent (40%) androgen receptor gene mutations in a series of 59 patients with a 46, XY disorder of sex development. J Clin Endocrinol Metab 95:1876–1888 Bagheri-Fam S, Sinclair AH, Koopman P, Harley VR (2010) Conserved regulatory modules in the Sox9 testis-specific enhancer predict roles for SOX, TCF/LEF, Forkhead, DMRT, and GATA proteins in vertebrate sex determination. Int J Biochem Cell Biol 42:472–477 Barbaro M, Oscarson M, Schoumans J et al (2007) Isolated 46, XY gonadal dysgenesis in two sisters caused by a Xp21.2 interstitial duplication containing the DAX1 gene. J Clin Endocrinol Metab 92:3305–3313 Barbaro M, Balsamo A, Anderlid BM et al (2009) Characterization of deletions at 9p affecting the candidate regions for sex reversal and deletion 9p syndrome by MLPA. Eur J Hum Genet 17:1439–1447 Barbaux S, Niaudet P, Gubler MC et al (1997) Donor splice-site mutations in WT1 are responsible for Frasier syndrome. Nat Genet 17:467–470 Bardoni B, Zanaria E, Guioli S et al (1994) A dosage sensitive locus at chromosome Xp21 is involved in male to female sex reversal. Nat Genet 7:497–501 Barrionuevo F, Bagheri-Fam S, Klattig J et al (2006) Homozygous inactivation of Sox9 causes complete XY sex reversal in mice. Biol Reprod 74:195–201 Barrionuevo F, Georg I, Scherthan H et al (2009) Testis cord differentiation after the sex determination stage is independent of Sox9 but fails in the combined absence of Sox9 and Sox8. Dev Biol 327:301–312 Bashamboo A, Ledig S, Wieacker P, Achermann JC, McElreavey K (2010) New technologies for the identification of novel genetic markers of disorders of sex development (DSD). Sex Dev 4:213–224 Benko S, Gordon CT, Mallet D et al (2011) Disruption of a long distance regulatory region upstream of SOX9 in isolated disorders of sex development. J Med Genet 48:825–830 Bernard P, Harley VR (2007) Wnt4 action in gonadal development and sex determination. Int J Biochem Cell Biol 39:31–43 Beverdam A, Koopman P (2006) Expression profiling of purified mouse gonadal somatic cells during the critical time window of sex determination reveals novel candidate genes for human sexual dysgenesis syndromes. Hum Mol Genet 15:417–431 Biason-Lauber A, Konrad D, Navratil F, Schoenle EJ (2004) A WNT4 mutation associated with Mullerian-duct regression and virilization in a 46, XX woman. N Engl J Med 351:792–798 Biason-Lauber A, Konrad D, Meyer M, DeBeaufort C, Schoenle EJ (2009) Ovaries and female phenotype in a girl with 46, XY karyotype and mutations in the CBX2 gene. Am J Hum Genet 84:658–663 Birk OS, Casiano DE, Wassif CA et al (2000) The LIM homeobox gene Lhx9 is essential for mouse gonad formation. Nature 403:909–913 Bishop CE, Whitworth DJ, Qin Y et al (2000) A transgenic insertion upstream of sox9 is associated with dominant XX sex reversal in the mouse. Nat Genet 26:490–494 Bitgood MJ, Shen L, McMahon AP (1996) Sertoli cell signaling by Desert hedgehog regulates the male germline. Curr Biol 6:298–304 Bogani D, Siggers P, Brixey R et al (2009) Loss of mitogen-activated protein kinase kinase kinase 4 (MAP3K4) reveals a requirement for MAPK signalling in mouse sex determination. PLoS Biol 7:e1000196 Bouma GJ, Washburn LL, Albrecht KH, Eicher EM (2007) Correct dosage of Fog2 and Gata4 transcription factors is critical for fetal testis development in mice. Proc Natl Acad Sci USA 104:14994–14999 Bowles J, Cooper L, Berkman J, Koopman P (1999) Sry requires a CAG repeat domain for male sex determination in Mus musculus. Nat Genet 22:405–408 Bowles J, Schepers G, Koopman P (2000) Phylogeny of the SOX family of developmental transcription factors based on sequence and structural indicators. Dev Biol 227:239–255 Bradford ST, Hiramatsu R, Maddugoda MP et al (2009) The cerebellin 4 precursor gene is a direct target of SRY and SOX9 in mice. Biol Reprod 80:1178–1188 Bullejos M, Koopman P (2001) Spatially dynamic expression of Sry in mouse genital ridges. Dev Dyn 221:201–205 Burris TP, Guo W, Le T, McCabe ER (1995) Identification of a putative steroidogenic factor-1 response element in the DAX-1 promoter. Biochem Biophys Res Commun 214:576–581 Calvari V, Bertini V, De Grandi A et al (2000) A new submicroscopic deletion that refines the 9p region for sex reversal. Genomics 65:203–212 Cameron FJ, Sinclair AH (1997) Mutations in SRY and SOX9: testis-determining genes. Hum Mutat 9:388–395 Canto P, Soderlund D, Reyes E, Mendez JP (2004) Mutations in the desert hedgehog (DHH) gene in patients with 46, XY complete pure gonadal dysgenesis. J Clin Endocrinol Metab 89:4480–4483 Canto P, Vilchis F, Soderlund D, Reyes E, Mendez JP (2005) A heterozygous mutation in the desert hedgehog gene in patients with mixed gonadal dysgenesis. Mol Hum Reprod 11:833–836 Cantu JM, Hernandez A, Vaca G et al (1981) Trisomy 22q12 leads to qter: “aneusomie de recombinaison” of a pericentric inversion. Ann Genet 24:37–40 Capel B (1998) Sex in the 90s: SRY and the switch to the male pathway. Annu Rev Physiol 60:497–523 Capel B (2000) The battle of the sexes. Mech Dev 92:89–103 Chaboissier MC, Kobayashi A, Vidal VI et al (2004) Functional analysis of Sox8 and Sox9 during sex determination in the mouse. Development 131:1891–1901 Chassot AA, Gregoire EP, Magliano M, Lavery R, Chaboissier MC (2008a) Genetics of ovarian differentiation: Rspo1, a major player. Sex Dev 2:219–227 Chassot AA, Ranc F, Gregoire EP et al (2008b) Activation of beta-catenin signaling by Rspo1 controls differentiation of the mammalian ovary. Hum Mol Genet 17:1264–1277 Clark AM, Garland KK, Russell LD (2000) Desert hedgehog (Dhh) gene is required in the mouse testis for formation of adult-type Leydig cells and normal development of peritubular cells and seminiferous tubules. Biol Reprod 63:1825–1838 Colvin JS, Green RP, Schmahl J, Capel B, Ornitz DM (2001) Male-to-female sex reversal in mice lacking fibroblast growth factor 9. Cell 104:875–889 Cory AT, Boyer A, Pilon N, Lussier JG, Silversides DW (2007) Presumptive pre-Sertoli cells express genes involved in cell proliferation and cell signalling during a critical window in early testis differentiation. Mol Reprod Dev 74:1491–1504 Cox JJ, Willatt L, Homfray T, Woods CG (2011) A SOX9 duplication and familial 46, XX developmental testicular disorder. N Engl J Med 364:91–93 Crispino JD, Lodish MB, Thurberg BL et al (2001) Proper coronary vascular development and heart morphogenesis depend on interaction of GATA-4 with FOG cofactors. Genes Dev 15:839–844 Crisponi L, Deiana M, Loi A et al (2001) The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome. Nat Genet 27:159–166 Crocker M, Coghill SB, Cortinho R (1988) An unbalanced autosomal translocation (7;9) associated with feminization. Clin Genet 34:70–73 D’Haene B, Attanasio C, Beysen D et al (2009) Disease-causing 7.4 kb cis-regulatory deletion disrupting conserved non-coding sequences and their interaction with the FOXL2 promotor: implications for mutation screening. PLoS Genet 5:e1000522 Das DK, Sanghavi D, Gawde H, Idicula-Thomas S, Vasudevan L (2011) Novel homozygous mutations in desert hedgehog gene in patients with 46, XY complete gonadal dysgenesis and prediction of its structural and functional implications by computational methods. Eur J Med Genet 54:e529–e534 de Santa Barbara P, Mejean C, Moniot B et al (2001) Steroidogenic factor-1 contributes to the cyclic-adenosine monophosphate down-regulation of human SRY gene expression. Biol Reprod 64:775–783 Erickson RP, Skinner S, Jacquet H et al (2003) Does chromosome 22 have anything to do with sex determination: further studies on a 46, XX,22q11.2 del male. Am J Med Genet A 123A:64–67 Evans T, Felsenfeld G (1989) The erythroid-specific transcription factor Eryf1: a new finger protein. Cell 58:877–885 Finelli P, Pincelli AI, Russo S et al (2007) Disruption of friend of GATA 2 gene (FOG-2) by a de novo t(8;10) chromosomal translocation is associated with heart defects and gonadal dysgenesis. Clin Genet 71:195–204 Foster JW, Brennan FE, Hampikian GK et al (1992) Evolution of sex determination and the Y chromosome: SRY-related sequences in marsupials. Nature 359:531–533 Foster JW, Dominguez-Steglich MA, Guioli S et al (1994) Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene. Nature 372:525–530 Fukami M, Wada Y, Miyabayashi K et al (2006) CXorf6 is a causative gene for hypospadias. Nat Genet 38:1369–1371 Garg V, Kathiriya IS, Barnes R et al (2003) GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature 424:443–447 Georg I, Bagheri-Fam S, Knower KC et al (2010) Mutations of the SRY-responsive enhancer of SOX9 are uncommon in XY gonadal dysgenesis. Sex Dev 4:321–325 Giese K, Cox J, Grosschedl R (1992) The HMG domain of lymphoid enhancer factor 1 bends DNA and facilitates assembly of functional nucleoprotein structures. Cell 69:185–195 Gordon CT, Tan TY, Benko S et al (2009) Long-range regulation at the SOX9 locus in development and disease. J Med Genet 46:649–656 Graves JA (2001) From brain determination to testis determination: evolution of the mammalian sex-determining gene. Reprod Fertil Dev 13:665–672 Grutzner F, Rens W, Tsend-Ayush E et al (2004) In the platypus a meiotic chain of ten sex chromosomes shares genes with the bird Z and mammal X chromosomes. Nature 432:913–917 Haber DA, Buckler AJ, Glaser T et al (1990) An internal deletion within an 11p13 zinc finger gene contributes to the development of Wilms' tumor. Cell 61:1257–1269 Hammes A, Guo JK, Lutsch G et al (2001) Two splice variants of the Wilms' tumor 1 gene have distinct functions during sex determination and nephron formation. Cell 106:319–329 Hanley NA, Hagan DM, Clement-Jones M et al (2000) SRY, SOX9, and DAX1 expression patterns during human sex determination and gonadal development. Mech Dev 91:403–407 Hannenhalli S, Kaestner KH (2009) The evolution of Fox genes and their role in development and disease. Nat Rev Genet 10:233–240 Heikinheimo M, Ermolaeva M, Bielinska M et al (1997) Expression and hormonal regulation of transcription factors GATA-4 and GATA-6 in the mouse ovary. Endocrinology 138:3505–3514 Heikkila M, Prunskaite R, Naillat F et al (2005) The partial female to male sex reversal in Wnt-4-deficient females involves induced expression of testosterone biosynthetic genes and testosterone production, and depends on androgen action. Endocrinology 146:4016–4023 Hirayama-Yamada K, Kamisago M, Akimoto K et al (2005) Phenotypes with GATA4 or NKX2.5 mutations in familial atrial septal defect. Am J Med Genet A 135:47–52 Hossain A, Saunders GF (2001) The human sex-determining gene SRY is a direct target of WT1. J Biol Chem 276:16817–16823 Houmard B, Small C, Yang L et al (2009) Global gene expression in the human fetal testis and ovary. Biol Reprod 81:438–443 Huang B, Wang S, Ning Y, Lamb AN, Bartley J (1999) Autosomal XX sex reversal caused by duplication of SOX9. Am J Med Genet 87:349–353 Hughes IA, Houk C, Ahmed SF, Lee PA (2006) Consensus statement on management of intersex disorders. J Pediatr Urol 2:148–162 Ingham PW (1998) Transducing hedgehog: the story so far. EMBO J 17:3505–3511 Jawaheer D, Juo SH, Le Caignec C et al (2003) Mapping a gene for 46, XY gonadal dysgenesis by linkage analysis. Clin Genet 63:530–535 Jordan BK, Mohammed M, Ching ST et al (2001) Up-regulation of WNT-4 signaling and dosage-sensitive sex reversal in humans. Am J Hum Genet 68:1102–1109 Jordan BK, Shen JH, Olaso R, Ingraham HA, Vilain E (2003) Wnt4 overexpression disrupts normal testicular vasculature and inhibits testosterone synthesis by repressing steroidogenic factor 1/beta-catenin synergy. Proc Natl Acad Sci USA 100:10866–10871 Kashimada K, Pelosi E, Chen H et al (2011) FOXL2 and BMP2 act cooperatively to regulate follistatin gene expression during ovarian development. Endocrinology 152:272–280 Katoh-Fukui Y, Tsuchiya R, Shiroishi T et al (1998) Male-to-female sex reversal in M33 mutant mice. Nature 393:688–692 Katoh-Fukui Y, Owaki A, Toyama Y et al (2005) Mouse Polycomb M33 is required for splenic vascular and adrenal gland formation through regulating Ad4BP/SF1 expression. Blood 106:1612–1620 Kim Y, Capel B (2006) Balancing the bipotential gonad between alternative organ fates: a new perspective on an old problem. Dev Dyn 235:2292–2300 Kim Y, Kobayashi A, Sekido R et al (2006) Fgf9 and Wnt4 act as antagonistic signals to regulate mammalian sex determination. PLoS Biol 4:e187 Kim S, Bardwell VJ, Zarkower D (2007a) Cell type-autonomous and non-autonomous requirements for Dmrt1 in postnatal testis differentiation. Dev Biol 307:314–327 Kim Y, Bingham N, Sekido R et al (2007b) Fibroblast growth factor receptor 2 regulates proliferation and Sertoli differentiation during male sex determination. Proc Natl Acad Sci USA 104:16558–16563 Kohler B, Lin L, Mazen I et al (2009) The spectrum of phenotypes associated with mutations in steroidogenic factor 1 (SF-1, NR5A1, Ad4BP) includes severe penoscrotal hypospadias in 46, XY males without adrenal insufficiency. Eur J Endocrinol 161:237–242 Koopman P (2005) Sex determination: a tale of two Sox genes. Trends Genet 21:367–370 Koopman P, Munsterberg A, Capel B, Vivian N, Lovell-Badge R (1990) Expression of a candidate sex-determining gene during mouse testis differentiation. Nature 348:450–452 Koopman P, Gubbay J, Vivian N, Goodfellow P, Lovell-Badge R (1991) Male development of chromosomally female mice transgenic for Sry. Nature 351:117–121 Kreidberg JA, Sariola H, Loring JM et al (1993) WT-1 is required for early kidney development. Cell 74:679–691 Kuo CT, Morrisey EE, Anandappa R et al (1997) GATA4 transcription factor is required for ventral morphogenesis and heart tube formation. Genes Dev 11:1048–1060 Le Caignec C, Delnatte C, Vermeesch JR et al (2007) Complete sex reversal in a WAGR syndrome patient. Am J Med Genet A 143A:2692–2695 Lecointre C, Pichon O, Hamel A et al (2009) Familial acampomelic form of campomelic dysplasia caused by a 960 kb deletion upstream of SOX9. Am J Med Genet A 149A:1183–1189 Lee DG, Han DH, Park KH, Baek M (2011) A novel WT1 gene mutation in a patient with Wilms' tumor and 46, XY gonadal dysgenesis. Eur J Pediatr 170(8):1079-82 Lourenco D, Brauner R, Lin L et al (2009) Mutations in NR5A1 associated with ovarian insufficiency. N Engl J Med 360:1200–1210 Lourenco D, Brauner R, Rybczynska M et al (2011) Loss-of-function mutation in GATA4 causes anomalies of human testicular development. Proc Natl Acad Sci USA 108:1597–1602 Lovell-Badge R (1992) The role of Sry in mammalian sex determination. CIBA Found Symp 165:162–179, discussion 179–182 Ludbrook LM, Harley VR (2004) Sex determination: a ‘window’ of DAX1 activity. Trends Endocrinol Metab 15:116–121 Luo X, Ikeda Y, Parker KL (1994) A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation. Cell 77:481–490 Lutfalla G, Roest Crollius H, Brunet FG, Laudet V, Robinson-Rechavi M (2003) Inventing a sex-specific gene: a conserved role of DMRT1 in teleost fishes plus a recent duplication in the medaka Oryzias latipes resulted in DMY. J Mol Evol 57(Suppl 1):S148–S153 Maatouk DM, DiNapoli L, Alvers A et al (2008) Stabilization of beta-catenin in XY gonads causes male-to-female sex-reversal. Hum Mol Genet 17:2949–2955 Manuylov NL, Smagulova FO, Leach L, Tevosian SG (2008) Ovarian development in mice requires the GATA4-FOG2 transcription complex. Development 135:3731–3743 Matson CK, Murphy MW, Sarver AL et al (2011) DMRT1 prevents female reprogramming in the postnatal mammalian testis. Nature 476:101–104 Matsuda M, Nagahama Y, Shinomiya A et al (2002) DMY is a Y-specific DM-domain gene required for male development in the medaka fish. Nature 417:559–563 Matzuk MM, Lu N, Vogel H et al (1995) Multiple defects and perinatal death in mice deficient in follistatin. Nature 374:360–363 McElreavey K, Rappaport R, Vilain E et al (1992) A minority of 46, XX true hermaphrodites are positive for the Y-DNA sequence including SRY. Hum Genet 90:121–125 Miyamoto Y, Taniguchi H, Hamel F, Silversides DW, Viger RS (2008) A GATA4/WT1 cooperation regulates transcription of genes required for mammalian sex determination and differentiation. BMC Mol Biol 9:44 Molkentin JD (2000) The zinc finger-containing transcription factors GATA-4, -5, and -6. Ubiquitously expressed regulators of tissue-specific gene expression. J Biol Chem 275:38949–38952 Molkentin JD, Lin Q, Duncan SA, Olson EN (1997) Requirement of the transcription factor GATA4 for heart tube formation and ventral morphogenesis. Genes Dev 11:1061–1072 Moniot B, Berta P, Scherer G, Sudbeck P, Poulat F (2000) Male specific expression suggests role of DMRT1 in human sex determination. Mech Dev 91:323–325 Morais da Silva S, Hacker A, Harley V et al (1996) Sox9 expression during gonadal development implies a conserved role for the gene in testis differentiation in mammals and birds. Nat Genet 14:62–68 Nanda I, Shan Z, Schartl M et al (1999) 300 million years of conserved synteny between chicken Z and human chromosome 9. Nat Genet 21:258–259 Nanda I, Kondo M, Hornung U et al (2002) A duplicated copy of DMRT1 in the sex-determining region of the Y chromosome of the medaka, Oryzias latipes. Proc Natl Acad Sci USA 99:11778–11783 Nemer G, Fadlalah F, Usta J et al (2006) A novel mutation in the GATA4 gene in patients with Tetralogy of Fallot. Hum Mutat 27:293–294 Nicholl RM, Grimsley L, Butler L et al (1994) Trisomy 22 and intersex. Arch Dis Child Fetal Neonatal Ed 71:F57–F58 Nishida H, Miyagawa S, Vieux-Rochas M et al (2008) Positive regulation of steroidogenic acute regulatory protein gene expression through the interaction between Dlx and GATA-4 for testicular steroidogenesis. Endocrinology 149:2090–2097 O’Bryan MK, Takada S, Kennedy CL et al (2008) Sox8 is a critical regulator of adult Sertoli cell function and male fertility. Dev Biol 316:359–370 Ogata T, Muroya K, Sasagawa I et al (2000) Genetic evidence for a novel gene(s) involved in urogenital development on 10q26. Kidney Int 58:2281–2290 Ottolenghi C, Moreira-Filho C, Mendonca BB et al (2001) Absence of mutations involving the LIM homeobox domain gene LHX9 in 46, XY gonadal agenesis and dysgenesis. J Clin Endocrinol Metab 86:2465–2469 Ottolenghi C, Omari S, Garcia-Ortiz JE et al (2005) Foxl2 is required for commitment to ovary differentiation. Hum Mol Genet 14:2053–2062 Ottolenghi C, Pelosi E, Tran J et al (2007) Loss of Wnt4 and Foxl2 leads to female-to-male sex reversal extending to germ cells. Hum Mol Genet 16:2795–2804 Pailhoux E, Vigier B, Chaffaux S et al (2001) A 11.7-kb deletion triggers intersexuality and polledness in goats. Nat Genet 29:453–458 Parma P, Radi O, Vidal V et al (2006) R-spondin1 is essential in sex determination, skin differentiation and malignancy. Nat Genet 38:1304–1309 Pearlman A, Loke J, Le Caignec C et al (2010) Mutations in MAP3K1 cause 46, XY disorders of sex development and implicate a common signal transduction pathway in human testis determination. Am J Hum Genet 87:898–904 Pelletier J, Bruening W, Li FP et al (1991) WT1 mutations contribute to abnormal genital system development and hereditary Wilms' tumour. Nature 353:431–434 Pierucci-Alves F, Clark AM, Russell LD (2001) A developmental study of the Desert hedgehog-null mouse testis. Biol Reprod 65:1392–1402 Pitteloud N, Quinton R, Pearce S et al (2007) Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism. J Clin Invest 117:457–463 Poirier C, Qin Y, Adams CP et al (2004) A complex interaction of imprinted and maternal-effect genes modifies sex determination in odd sex (Ods) mice. Genetics 168:1557–1562 Polanco JC, Wilhelm D, Davidson TL, Knight D, Koopman P (2010) Sox10 gain-of-function causes XX sex reversal in mice: implications for human 22q-linked disorders of sex development. Hum Mol Genet 19:506–516 Pop R, Conz C, Lindenberg KS et al (2004) Screening of the 1 Mb SOX9 5′ control region by array CGH identifies a large deletion in a case of campomelic dysplasia with XY sex reversal. J Med Genet 41:e47 Porter FD (2008) Smith–Lemli–Opitz syndrome: pathogenesis, diagnosis and management. Eur J Hum Genet 16:535–541 Poulat F, Girard F, Chevron MP et al (1995) Nuclear localization of the testis determining gene product SRY. J Cell Biol 128:737–748 Raymond CS, Shamu CE, Shen MM et al (1998) Evidence for evolutionary conservation of sex-determining genes. Nature 391:691–695 Raymond CS, Parker ED, Kettlewell JR et al (1999) A region of human chromosome 9p required for testis development contains two genes related to known sexual regulators. Hum Mol Genet 8:989–996 Raymond CS, Murphy MW, O'Sullivan MG, Bardwell VJ, Zarkower D (2000) Dmrt1, a gene related to worm and fly sexual regulators, is required for mammalian testis differentiation. Genes Dev 14:2587–2595 Refai O, Friedman A, Terry L et al (2010) De novo 12;17 translocation upstream of SOX9 resulting in 46, XX testicular disorder of sex development. Am J Med Genet A 152A:422–426 Sadovsky Y, Dorn C (2000) Function of steroidogenic factor 1 during development and differentiation of the reproductive system. Rev Reprod 5:136–142 Schepers GE, Teasdale RD, Koopman P (2002) Twenty pairs of sox: extent, homology, and nomenclature of the mouse and human sox transcription factor gene families. Dev Cell 3:167–170 Schepers G, Wilson M, Wilhelm D, Koopman P (2003) SOX8 is expressed during testis differentiation in mice and synergizes with SF1 to activate the Amh promoter in vitro. J Biol Chem 278:28101–28108 Schlaubitz S, Yatsenko SA, Smith LD et al (2007) Ovotestes and XY sex reversal in a female with an interstitial 9q33.3–q34.1 deletion encompassing NR5A1 and LMX1B causing features of Genitopatellar syndrome. Am J Med Genet A 143A:1071–1081 Schmahl J, Kim Y, Colvin JS, Ornitz DM, Capel B (2004) Fgf9 induces proliferation and nuclear localization of FGFR2 in Sertoli precursors during male sex determination. Development 131:3627–3636 Schnack TH, Zdravkovic S, Myrup C et al (2008) Familial aggregation of hypospadias: a cohort study. Am J Epidemiol 167:251–256 Seeherunvong T, Perera EM, Bao Y et al (2004) 46, XX sex reversal with partial duplication of chromosome arm 22q. Am J Med Genet A 127A:149–151 Sekido R, Lovell-Badge R (2008) Sex determination involves synergistic action of SRY and SF1 on a specific Sox9 enhancer. Nature 453:930–934 Sekido R, Bar I, Narvaez V, Penny G and Lovell-Badge R (2004) SOX9 is up-regulated by the transient expression of SRY specifically in Sertoli cell precursors. Dev Biol 274:271–279 Sharp AJ, Selzer RR, Veltman JA et al (2007) Characterization of a recurrent 15q24 microdeletion syndrome. Hum Mol Genet 16:567–572 Shinoda K, Lei H, Yoshii H et al (1995) Developmental defects of the ventromedial hypothalamic nucleus and pituitary gonadotroph in the Ftz-F1 disrupted mice. Dev Dyn 204:22–29 Siggers P, Smith L, Greenfield A (2002) Sexually dimorphic expression of Gata-2 during mouse gonad development. Mech Dev 111:159–162 Sinclair AH, Berta P, Palmer MS et al (1990) A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif. Nature 346:240–244 Smith CA, McClive PJ, Western PS, Reed KJ, Sinclair AH (1999) Conservation of a sex-determining gene. Nature 402:601–602 Smith CA, Shoemaker CM, Roeszler KN et al (2008) Cloning and expression of R-Spondin1 in different vertebrates suggests a conserved role in ovarian development. BMC Dev Biol 8:72 Smith CA, Roeszler KN, Ohnesorg T et al (2009) The avian Z-linked gene DMRT1 is required for male sex determination in the chicken. Nature 461:267–271 Smyk M, Berg JS, Pursley A et al (2007) Male-to-female sex reversal associated with an approximately 250 kb deletion upstream of NR0B1 (DAX1). Hum Genet 122:63–70 Sock E, Schmidt K, Hermanns-Borgmeyer I, Bosl MR, Wegner M (2001) Idiopathic weight reduction in mice deficient in the high-mobility-group transcription factor Sox8. Mol Cell Biol 21:6951–6959 Stark K, Vainio S, Vassileva G, McMahon AP (1994) Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372:679–683 Sultan C, Biason-Lauber A, Philibert P (2009) Mayer–Rokitansky–Kuster–Hauser syndrome: recent clinical and genetic findings. Gynecol Endocrinol 25:8–11 Sutton E, Hughes J, White S et al (2011) Identification of SOX3 as an XX male sex reversal gene in mice and humans. J Clin Invest 121:328–341 Swain A, Lovell-Badge R (1999) Mammalian sex determination: a molecular drama. Genes Dev 13:755–767 Taylor HS, Block K, Bick DP, Sherins RJ, Layman LC (1999) Mutation analysis of the EMX2 gene in Kallmann's syndrome. Fertil Steril 72:910–914 Temel SG, Gulten T, Yakut T et al (2007) Extended pedigree with multiple cases of XX sex reversal in the absence of SRY and of a mutation at the SOX9 locus. Sex Dev 1:24–34 Tevosian SG, Albrecht KH, Crispino JD et al (2002) Gonadal differentiation, sex determination and normal Sry expression in mice require direct interaction between transcription partners GATA4 and FOG2. Development 129:4627–4634 Tomaselli S, Megiorni F, De Bernardo C et al (2008) Syndromic true hermaphroditism due to an R-spondin1 (RSPO1) homozygous mutation. Hum Mutat 29:220–226 Tomaselli S, Megiorni F, Lin L et al (2011) Human RSPO1/R-spondin1 is expressed during early ovary development and augments beta-catenin signaling. PLoS One 6:e16366 Tomita-Mitchell A, Maslen CL, Morris CD, Garg V, Goldmuntz E (2007) GATA4 sequence variants in patients with congenital heart disease. J Med Genet 44:779–783 Tomizuka K, Horikoshi K, Kitada R et al (2008) R-spondin1 plays an essential role in ovarian development through positively regulating Wnt-4 signaling. Hum Mol Genet 17:1278–1291 Trautmann E, Guerquin MJ, Duquenne C et al (2008) Retinoic acid prevents germ cell mitotic arrest in mouse fetal testes. Cell Cycle 7:656–664 Tremblay JJ, Robert NM, Viger RS (2001) Modulation of endogenous GATA-4 activity reveals its dual contribution to Mullerian inhibiting substance gene transcription in Sertoli cells. Mol Endocrinol 15:1636–1650 Uhlenhaut NH, Jakob S, Anlag K et al (2009) Somatic sex reprogramming of adult ovaries to testes by FOXL2 ablation. Cell 139:1130–1142 Umehara F, Tate G, Itoh K et al (2000) A novel mutation of desert hedgehog in a patient with 46, XY partial gonadal dysgenesis accompanied by minifascicular neuropathy. Am J Hum Genet 67:1302–1305 Vainio S, Heikkila M, Kispert A, Chin N, McMahon AP (1999) Female development in mammals is regulated by Wnt-4 signalling. Nature 397:405–409 Val P, Swain A (2010) Gene dosage effects and transcriptional regulation of early mammalian adrenal cortex development. Mol Cell Endocrinol 323:105–114 van Silfhout A, Boot AM, Dijkhuizen T et al (2009) A unique 970 kb microdeletion in 9q33.3, including the NR5A1 gene in a 46, XY female. Eur J Med Genet 52:157–160 Veitia RA, Nunes M, Quintana-Murci L et al (1998) Swyer syndrome and 46, XY partial gonadal dysgenesis associated with 9p deletions in the absence of monosomy-9p syndrome. Am J Hum Genet 63:901–905 Vetro A, Ciccone R, Giorda R et al (2011) XX males SRY negative: a confirmed cause of infertility. J Med Genet 48:710–712 Vidal VP, Chaboissier MC, de Rooij DG, Schedl A (2001) Sox9 induces testis development in XX transgenic mice. Nat Genet 28:216–217 Viger RS, Mertineit C, Trasler JM, Nemer M (1998) Transcription factor GATA-4 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 Viger RS, Guittot SM, Anttonen M, Wilson DB, Heikinheimo M (2008) Role of the GATA family of transcription factors in endocrine development, function, and disease. Mol Endocrinol 22:781–798 Vinci G, Chantot-Bastaraud S, El Houate B et al (2007) Association of deletion 9p, 46, XY gonadal dysgenesis and autistic spectrum disorder. Mol Hum Reprod 13:685–689 Wagner T, Wirth J, Meyer J et al (1994) Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9. Cell 79:1111–1120 Wainwright EN, Wilhelm D (2010) The game plan: cellular and molecular mechanisms of mammalian testis development. Curr Top Dev Biol 90:231–262 White S, Ohnesorg T, Notini A et al (2011) Copy number variation in patients with disorders of sex development due to 46, XY gonadal dysgenesis. PLoS One 6:1–10 Wieacker P, Volleth M (2007) WNT4 and RSPO1 are not involved in a case of male-to-female sex reversal with partial duplication of 1p. Sex Dev 1:111–113 Wilhelm D, Englert C (2002) The Wilms tumor suppressor WT1 regulates early gonad development by activation of Sf1. Genes Dev 16:1839–1851 Wilhelm D, Martinson F, Bradford S et al (2005) Sertoli cell differentiation is induced both cell-autonomously and through prostaglandin signaling during mammalian sex determination. Dev Biol 287:111–124 Wilhelm D, Hiramatsu R, Mizusaki H et al (2007) SOX9 regulates prostaglandin D synthase gene transcription in vivo to ensure testis development. J Biol Chem 282:10553–10560 Wilson MJ, Jeyasuria P, Parker KL, Koopman P (2005) The transcription factors steroidogenic factor-1 and SOX9 regulate expression of Vanin-1 during mouse testis development. J Biol Chem 280:5917–5923 Yao HH, Capel B (2002) Disruption of testis cords by cyclopamine or forskolin reveals independent cellular pathways in testis organogenesis. Dev Biol 246:356–365 Yao HH, Whoriskey W, Capel B (2002) Desert hedgehog/patched 1 signaling specifies fetal Leydig cell fate in testis organogenesis. Genes Dev 16:1433–1440 Yao HH, Matzuk MM, Jorgez CJ et al (2004) Follistatin operates downstream of Wnt4 in mammalian ovary organogenesis. Dev Dyn 230:210–215 Yoshida M, Suda Y, Matsuo I et al (1997) Emx1 and Emx2 functions in development of dorsal telencephalon. Development 124:101–111