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Genetic regulation of mammalian gonad development

Key Points

  • The critical testis-determining genes are Sry and Sox9; however, many genes upstream of Sry and downstream of Sry and Sox9 are also important for correct testis development

  • Novel factors have been identified in the known pathways of the testis-determining network, including Six1, Six4, Map3k4, Gadd45g and Hhat

  • Ovarian development lacks a single genetic switch; however, genes such as Rspo1, Foxl2, Wnt4 and Ctnnb1 seem to be essential for correct ovary development

  • Both the testis-determining and ovary-determining pathways have active gene networks that must be maintained throughout life by suppression of the opposing pathway

  • As well as regulation of gene expression by transcription factors, other types of gene control, such as noncoding RNAs and epigenetic modification, are required for gonad development

Abstract

Sex-specific gonadal development starts with formation of the bipotential gonad, which then differentiates into either a mature testis or an ovary. This process is dependent on activation of either the testis-specific or the ovary-specific pathway while the opposite pathway is continuously repressed. A network of transcription factors tightly regulates initiation and maintenance of these distinct pathways; disruption of these networks can lead to disorders of sex development in humans and male-to-female or female-to-male sex reversal in mice. Sry is the Y-linked master switch that is both required and sufficient to drive the testis-determining pathway. Another key component of the testis pathway is Sox9, which acts immediately downstream of Sry. In contrast to the testis pathway, no single sex-determining factor has been identified in the ovary pathway; however, multiple genes, such as Foxl2, Rspo1, Ctnnb1, and Wnt4, seem to work synergistically and in parallel to ensure proper ovary development. Our understanding of the regulatory networks that underpin testis and ovary development has grown substantially over the past two decades.

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Figure 1: Genes and pathways required for the development of the bipotential gonad.
Figure 2: Genes and pathways required for testis development and differentiation.
Figure 3: Genes and pathways required for ovary development and differentiation.
Figure 4: Interactions between the testis-specific and ovary-specific pathways during embryonic development and adulthood.

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Acknowledgements

The authors' research work was supported by The National Health and Medical Research Council, Australia (program grant #546517 and project grant #1031214); the Helen Macpherson Smith Trust (partnership grant #6846); the Ian Potter Centre for Genomics and Personalised Medicine; and the Victorian Government's Operational Infrastructure Support Program.

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Eggers, S., Ohnesorg, T. & Sinclair, A. Genetic regulation of mammalian gonad development. Nat Rev Endocrinol 10, 673–683 (2014). https://doi.org/10.1038/nrendo.2014.163

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