SRY, Sex Determination and Gonadal Differentiation

Abstract

The commitment to develop into a male or female embryo is dependent on whether testes or ovaries develop from the primordial gonads. This decision is in turn controlled by the function of a gene, SRY, found on the Y chromosome in mammals. The proper expression and function of SRY in supporting cell precursors induces a cascade of gene expression that causes these cells to differentiate into Sertoli cells. Subsequently, Sertoli cells orchestrate the development of all other cell types resulting in the formation of testes, which produce hormones required for other aspects of male development. In the absence of SRY, or if SRY function is impaired, the supporting cells differentiate into granulosa cells, ovaries form and the embryo develops as a female.

Key Concepts:

  • Sex determination in mammals depends on the presence or absence of the Y‚Äźchromosome gene SRY.

  • SRY induces a program of gene expression in the sexually ambiguous primordial gonads of the embryo to induce differentiation of Sertoli cells.

  • Once Sertoli cells form, they influence other bipotential cell lineages to differentiate into cell types appropriate for a testis.

  • When SRY is absent or dysfunctional, a default genetic program instead causes granulosa cell differentiation and ovary development.

  • Mutations in genes involved in the testis and ovarian differentiation programs can cause human disorders of sex development.

Keywords: sex determination; SRY; sex reversal; Y chromosome; testis development; ovary development

Figure 1.

Sex reversal in humans caused by abnormal X–Y exchange. (a) Normal X–Y exchange. During male meiosis, the X and Y chromosomes align and genetically recombine (crossover; blue double‐headed arrow) within the pseudoautosomal or X–Y pairing region, shown in yellow. (b) Abnormal X–Y exchange, in which recombination occurs outside the X–Y pairing region, resulting in transfer of some Y chromosomal DNA to the X chromosome. The abnormal X chromosome thus generated is capable of directing male development, indicating that the testis‐determining locus TDF must reside close to the pseudoautosomal boundary on the human Y chromosome. Analysis of the 35 kb Y‐derived region present on an X chromosome in four XX males led to the identification of SRY, the Y‐linked testis‐determining gene.

Figure 2.

Structure of the early fetal testis. (a) Schematic diagram of a 13.5 dpc mouse testis showing development of testis cords. The testis is attached to a mesonephros, which contains the Wolffian duct that later develops to form the vas deferens. (b) The area demarcated by a rectangle in (a) is enlarged here, which shows the cell types that make up the testis cords (peritubular myoid cells that help maintain cord integrity and later provide the pulsatory contractions required for export of sperm; germ cells that later develop into sperm; and Sertoli cells whose processes intertwine and provide support and nourishment for the germ cells) and the interstitium between the cords (steroid‐producing Leydig cells and other cells such as macrophages and blood vessels). Sry is expressed in the precursors to the Sertoli cells, which then differentiate and signal to other immature cell types to regulate their differentiation and organisation.

Figure 3.

Cellular and molecular interactions during gonadal induction. Effector genes or gene products are shown in boxes and are described in the text. AMH, anti‐Müllerian hormone; DHT, dihydrotestosterone.

close

References

Arango NA, Lovell‐Badge R and 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.

Barrionuevo F, Bagheri‐Fam S, Klattig J et al. (2006) Homozygous inactivation of Sox9 causes complete XY sex reversal in mice. Biology of Reproduction 74: 195–201.

Barsoum IB and Yao HH (2010) Fetal Leydig cells: progenitor cell maintenance and differentiation. Journal of Andrology 31: 11–15.

Bowles J, Feng CW, Spiller C et al. (2010) FGF9 suppresses meiosis and promotes male germ cell fate in mice. Develeopmental Cell 19: 440–449.

Bowles J, Knight D, Smith C et al. (2006) Retinoid signaling determines germ cell fate in mice. Science 312: 596–600.

Bowles J, Schepers G and Koopman P (2000) Phylogeny of the SOX family of developmental transcription factors based on sequence and structural indicators. Developmental Biology 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. Biology of Reproduction 80: 1178–1188.

Brennan J, Karl J and Capel B (2002) Divergent vascular mechanisms downstream of Sry establish the arterial system in the XY gonad. Developmental Biology 244: 418–428.

Bridges CB and Anderson EG (1925) Crossing over in the X Chromosomes of Triploid Females of DROSOPHILA MELANOGASTER. Genetics 10: 418–441.

Bullejos M and Koopman P (2001) Spatially dynamic expression of Sry in mouse genital ridges. Developmental Dynamics 221: 201–205.

Bullejos M and Koopman P (2004) Germ cells enter meiosis in a rostro‐caudal wave during development of the mouse ovary. Molecular Reproduction and Development 68: 422–428.

Capel B, Albrecht KH, Washburn LL and Eicher EM (1999) Migration of mesonephric cells into the mammalian gonad depends on Sry. Mechanisms of Development 84: 127–131.

Caricasole A, Duarte A, Larsson SH et al. (1996) RNA binding by the Wilms tumor suppressor zinc finger proteins. Proceedings of the National Academy of Sciences of the USA 93: 7562–7566.

Chaboissier MC, Kobayashi A, Vidal VIP et al. (2004) Functional analysis of Sox8 and Sox9 during sex determination in the mouse. Development 131: 1891–1901.

Chassot AA, Ranc F, Gregoire EP et al. (2008) Activation of beta‐catenin signaling by Rspo1 controls differentiation of the mammalian ovary. Human Molecular Genetics 17: 1264–1277.

Chiquoine AD (1954) The identification, origin, and migration of the primordial germ cells in the mouse embryo. Anatomical Record 118: 135–146.

Combes AN, Lesieur E, Harley VR et al. (2009a) Three‐dimensional visualization of testis cord morphogenesis, a novel tubulogenic mechanism in development. Developmental Dynamics 238: 1033–1041.

Combes AN, Wilhelm D, Davidson T et al. (2009b) Endothelial cell migration directs testis cord formation. Developmental Biology 326: 112–120.

Dolci S and De Felici M (1990) A study of meiosis in chimeric mouse fetal gonads. Development 109: 37–40.

Eicher EM, Washburn LL, Schork NJ et al. (1996) Sex‐determining genes on mouse autosomes identified by linkage analysis of C57BL/6J‐YPOS sex reversal. Nature Genetics 14: 206–209.

Giese K, Pagel J and Grosschedl R (1994) Distinct DNA‐binding properties of the high mobility group domain of murine and human SRY sex‐determining factors. Proceedings of the National Academy of Sciences of the USA 91: 3368–3372.

Hammes A, Guo JK, Lutsch G et al. (2001) Two splice variants of the Wilms' tumor gene have distinct functions during sex determination and nephron formation. Cell 106: 319–329.

Jost A (1947) Recherches sur la différenciation sexuelle de l'embryon de lapin. III. Rôle des gonades foetales dans la différenciation sexuelle somatique. Archives d'Anatomie Microscopique et de Morphologie Experimentale 36: 271–315.

Kim Y, Kobayashi A, Sekido R et al. (2006) Fgf9 and Wnt4 act as antagonistic signals to regulate mammalian sex determination. PLoS Biology 4: e187.

Koopman P, Gubbay J, Vivian N, Goodfellow P and Lovell‐Badge R (1991) Male development of chromosomally female mice transgenic for SRY. Nature 351: 117–121.

Koubova J, Menke DB, Zhou Q et al. (2006) Retinoic acid regulates sex‐specific timing of meiotic initiation in mice. Proceedings of the National Academy of Sciences of the USA 103: 2474–2479.

Kreidberg JA, Sariola H, Loring JM et al. (1993) WT‐1 is required for early kidney development. Cell 74: 679–691.

Loffler KA, Zarkower D and Koopman P (2003) Etiology of ovarian failure in blepharophimosis ptosis epicanthus inversus syndrome: FOXL2 is a conserved, early acting gene in vertebrate ovarian development. Endocrinology 144: 3237–3243.

Martineau J, Nordqvist K, Tilmann C, Lovell‐Badge R and Capel B (1997) Male‐specific cell migration into the developing gonad. Current Biology 7: 958–968.

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. Nature Genetics 14: 62–68.

Parma P, Pailhoux E and Cotinot C (1999) Reverse transcription‐polymerase chain reaction analysis of genes involved in gonadal differentiation in pigs. Biology of Reprodruction 61: 741–748.

Pontiggia A, Rimini R, Harley VR et al. (1994) Sex‐reversing mutations affect the architecture of SRY‐DNA complexes. EMBO Journal 13: 6115–6124.

de Santa Barbara P, Bonneaud N, Boizet B et al. (1998) Direct interaction of SRY‐related protein SOX9 and steroidogenic factor 1 regulates transcription of the human anti‐Müllerian hormone gene. Molecular and Cellular Biology 18: 6653–6665.

Schmahl J, Eicher E, Washburn L and Capel B (2000) Sry induces cell proliferation in the mouse gonad. Development 127: 65–73.

Sekido R and 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. Developmental Biology 274: 271–279.

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.

Swain A, Narvaez V, Burgoyne PS, Camerino G and Lovell‐Badge R (1998) Dax1 antagonizes SRY action in mammalian sex determination. Nature 391: 761–767.

Tomizuka K, Horikoshi K, Kitada R et al. (2008) R‐spondin1 plays an essential role in ovarian development through positively regulating Wnt‐4 signaling. Human Molecular Genetics 17: 1278–1291.

Vainio S, Heikkila M, Kispert A, Chin N and McMahon AP (1999) Female development in mammals is regulated by Wnt‐4 signalling. Nature 397: 405–409.

Wilhelm D and Englert C (2002) The Wilms tumor suppressor WT1 regulates early gonad development by activation of Sf1. Genes & Development 16: 1839–1851.

Wilhelm D, Hiramatsu R, Mizusaki H et al. (2007) SOX9 regulates prostaglandin D synthase gene transcription in vivo to ensure testis development. Journal of Biological Chemistry 282: 10553–10560.

Wilson MJ, Jeyasuria P, Parker KL and Koopman P (2005) The transcription factors steroidogenic factor‐1 and SOX9 regulate expression of Vanin‐1 during mouse testis development. Journal of Biological Chemistry 280: 5917–5923.

Yu RN, Ito M, Saunders TL, Camper SA and Jameson JL (1998) Role of Ahch in gonadal development and gametogenesis. Nature Genetics 20: 353–357.

Zanaria E, Muscatelli F, Bardoni B et al. (1994) An unusual member of the nuclear hormone receptor superfamily responsible for X‐linked adrenal hypoplasia congenita. Nature 372: 635–641.

Further Reading

Brennan J and Capel B (2004) One tissue, two fates: molecular genetic events that underlie testis versus ovary development. Nature Reviews Genetics 5: 509–521.

Koopman P (1999) Sry and Sox9: mammalian testis‐determining genes. Cellular and Molecular Life Sciences 55: 839–856.

McLaren A (2003) Primordial germ cells in the mouse. Developmental Biology 262: 1–15.

Wilhelm D and Koopman P (2006) The makings of maleness: towards an integrated view of male sexual development. Nature Reviews Genetics 7: 620–631.

Wilhelm D, Palmer S and Koopman P (2007) Sex determination and gonadal development in mammals. Physiological Reviews 87: 1–28.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Koopman, Peter, and Wilhelm, Dagmar(Nov 2011) SRY, Sex Determination and Gonadal Differentiation. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001144.pub3]