Development of the Mammalian Gonad: Key Sex‐Determining Genes in Mice and Humans


Sex determination is the process by which an embryo commits to the male or female gonadal fate. Our understanding of mammalian sex determination is dominated by the consideration of data from humans and mouse models. Humans and mice share important elements of their reproductive biology, and therefore experimentation in the mouse offers the prospect of detailed mechanistic insights into typical and atypical human sexual development. Recent studies reveal a high degree of conservation in the roles played by sex‐determining genes in mice and humans, but also important differences. Key themes that have emerged from mouse genetics studies include the mutually antagonistic roles of testis‐ and ovary‐determining genes and the requirement to maintain these long after the primary sex‐determining event. The advent of technologies such as next‐generation sequencing and genome editing promises to shed more light on the causes of disorders of sex development in humans, as well as fundamental mechanisms in cell fate commitment in the mammalian gonad.

Key Concepts

  • The mammalian gonad (testis or ovary) develops from a bipotential primordium in which genes associated with later sexual differentiation are expressed.
  • The testis‐ and ovary‐determining gene networks are mutually antagonistic during primary sex determination.
  • The maintenance of cell identity in the differentiated adult gonad requires continued inhibition of opposing genetic pathways.
  • Interpreting the nature of mutations associated with human genetic disease, including disorders of sex development (DSD), is aided by the generation and study of mouse models.

Keywords: sex determination; cell fate commitment; testis; ovary; embryonic gonad; disorders of sex development; mouse genetics; mouse models; developmental biology

Figure 1. Overview of the key cellular events in mammalian testis determination. (a) The genital ridge (GR) is a derivative of intermediate mesoderm and contains the gonad and reproductive tract primordia. The gonad forms on the ventromedial surface of the mesonephros (M) at around 10.0 dpc through proliferation of cells in the coelomic epithelium (CE). At around 11.5 dpc, the gonad (G) is bipotential, retaining the capacity to develop into a testis or ovary. (b) In XY gonadal somatic cells at 11.5 dpc, SRY initiates testis development. The core testis‐determining gene network causes differentiation of Sertoli cells from supporting cell precursors, and signals from these control migration of endothelial cells from the adjacent mesonephros to form the coelomic vessel (CV). Testis cords (TCs), comprising primordial germ cells and Sertoli cells, are visible under the light microscope by 13.5 dpc. The tissue between the cords, the interstitium (shaded), contains fetal Leydig cells, which produce androgens that masculinise other fetal structures. (c) Wholemount in situ hybridisation (WMISH) of a 14.5 dpc XY gonad with the Sertoli cell marker Sox9 reveals the TCs. (d) In the XX gonads, in the absence of SRY, canonical WNT signals block cellular migration into the gonad and instead promote differentiation of granulosa cells and entry of germ cells into meiosis. In contrast to the testis, little tissue remodelling is apparent down the light microscope. In developing ovaries, granulsoa cells and germ cells associate to form ovigerous cords (OC), the precursors of follicles. (e) The presence of ovarian somatic cells is revealed by WMISH of a 13.5 dpc XX gonad with a Wnt4 probe.
Figure 2. The testis‐ and ovary‐determining gene networks oppose each other during mammalian sex determination. In XY supporting cell precursors, testis determination is initiated by SRY expression. SRY upregulates SOX9, which in turn activates FGF9/FGFR2 – a linear genetic pathway. These FGF signals maintain high levels of SOX9 expression, but do so partly by opposing the activity of WNT4. SOX9 antagonises RSPO1, β‐catenin (CTNNB1) and FOXL2. In addition to inhibitory roles, SOX9 activates PTGDS, AMH and CYP26B1. The latter is crucial in preventing retinoic acid‐mediated entry of germ cells into meiosis. In XX somatic cells, the absence of SRY results in canonical WNT signals and FOXL2 acting independently to inhibit SRY‐SOX9‐FGF9 and thereby promote granulosa cell differentiation and germ cell meiotic entry. A role for GATA4 is also reported. WNT signals upregulate expression of follistatin (FST). Regulatory links to other testis‐ and ovary‐determining genes remain to be identified (question marks), based partly on the large number of undiagnosed cases of 46,XY DSD in humans.


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Further Reading

For a series of recent review articles covering different aspects of sexual development in vertebrates more broadly, see the special issue of Sexual Development (vol. 8, no. 5, 2014): “Sexual Differentiation of Vertebrate Reproductive Organs”.

More details about SRY, its regulation and function, can be found in two reviews: Larney et al. (2014) Development (DOI: 10.1242/dev.107052.) and Kashimada & Koopman (2010) Development (DOI: 10.1242/dev.048983).

The control of male and female germ cell fate during mammalian gonadogenesis is covered by Rossito et al. (2015) Seminars in Developmental Biology (DOI: 10.1016/j.semcdb.2015.09.014) and Spiller et al. (2012) International Journal of Developmental Biology (DOI: 10.1387/ijdb.120142pk), respectively.

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Warr, Nick, and Greenfield, Andy(Feb 2016) Development of the Mammalian Gonad: Key Sex‐Determining Genes in Mice and Humans. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0025355]