Transcriptional regulation of testis differentiation

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Homo sapiens
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In humans, primordial germ cells (PGCs) are specified about 2 weeks after fertilization, a time before gastrulation (reviewed in Svingen and Koopman 2013, Mäkelä et al. 2019). PGCs are initially located extraembryonically and then migrate to colonize the gonadal ridges (genital ridges) of the embryo during the fifth week after fertilization. At this time, either ovaries and testes can originate from the gonadal ridges. That is, the cells of the gonadal ridges are initially bipotential and remain bipotential until about 42 days after conception, when transient expression of the SRY gene located on the Y chromosome in male embryos is initiated in some somatic cells of the gonadal primordium (reviewed in Sekido and Lovell-Badge 2013, Barrionuevo et al. 2013, Svingen et al. 2013, Mäkelä et al. 2019).
The transcription factors WT1, GATA4, ZFPM2 (FOG2), and the nuclear receptor NR5A1 (SF1) activate transcription of SRY (Shimamura et al. 1997, Hossain and Saunders 2001, De Santa Barbara et al. 2001, Miyamoto et al. 2008, and inferred from mouse homologs). SRY and NR5A1 then activate transcription of SOX9, one of the master regulators of testis development and maintenance (Knower et al. 2011, Croft et al. 2018, inferred from mouse homologs, reviewed in Gonen and Lovell-Badge 2019). Regulation of genes by SRY and then, when expression of SRY decreases, by SOX9 causes the specification of Sertoli cells that further organize formation of the testis by encasing the primordial germ cells in protocords, which then form fully developed testis cords.
SOX9 directly activates its own promoter to maintain SOX9 expression through development and into adulthood (Croft et al. 2018, and inferred from mouse homologs). SOX9 and GATA4 directly activate DMRT1 (inferred from mouse homologs), which maintains testis specification by maintaining expression of SOX9 and other testis-related genes. DMRT1 also acts to suppress ovarian specification by binding and repressing FOXL2 and WNT4 genes (inferred from mouse homologs). SOX9 directly activates FGF9 (inferred from mouse homologs), which acts via FGFR2 to maintain SOX9 expression, and PTGDS (inferred from mouse homologs), which converts Prostaglandin H2 to Prostaglandin D2, a critical hormone-like lipid that recruits supporting cells to Sertoli cells and acts indirectly to maintain SOX9 expression. SOX9, NR5A1, and GATA4 directly activate AMH (De Santa Barbara et al. 1998, and inferred from mouse homologs), an extracellular signaling molecule which causes regression of the Muellerian duct of the female reproductive system. SOX9 also directly activates many other genes, including DHH (Rahmoun et al. 2017, and inferred from mouse homologs), an intercellular signaling molecule required for testis formation.

Literature References
PubMed ID Title Journal Year
19647095 SOX E genes: SOX9 and SOX8 in mammalian testis development

Barrionuevo, FJ, Scherer, G

Int. J. Biochem. Cell Biol. 2010
28472341 In mammalian foetal testes, SOX9 regulates expression of its target genes by binding to genomic regions with conserved signatures

Rahmoun, M, Lavery, R, Laurent-Chaballier, S, Bellora, N, Philip, GK, Rossitto, M, Symon, A, Pailhoux, E, Cammas, F, Chung, J, Bagheri-Fam, S, Murphy, M, Bardwell, V, Zarkower, D, Boizet-Bonhoure, B, Clair, P, Harley, VR, Poulat, F

Nucleic Acids Res. 2017
23018237 Genes promoting and disturbing testis development

Barrionuevo, FJ, Burgos, M, Scherer, G, Jiménez, R

Histol. Histopathol. 2012
9774680 Direct interaction of SRY-related protein SOX9 and steroidogenic factor 1 regulates transcription of the human anti-Müllerian hormone gene

De Santa Barbara, P, Bonneaud, N, Boizet, B, Desclozeaux, M, Moniot, B, Sudbeck, P, Scherer, G, Poulat, F, Berta, P

Mol. Cell. Biol. 1998
11278460 The human sex-determining gene SRY is a direct target of WT1

Hossain, A, Saunders, GF

J. Biol. Chem. 2001
24240231 Building the mammalian testis: origins, differentiation, and assembly of the component cell populations

Svingen, T, Koopman, P

Genes Dev. 2013
30999977 The regulation of Sox9 expression in the gonad

Gonen, N, Lovell-Badge, R

Curr. Top. Dev. Biol. 2019
30552336 Human sex reversal is caused by duplication or deletion of core enhancers upstream of SOX9

Croft, B, Ohnesorg, T, Hewitt, J, Bowles, J, Quinn, A, Tan, J, Corbin, V, Pelosi, E, van den Bergen, J, Sreenivasan, R, Knarston, I, Robevska, G, Vu, DC, Hutson, J, Harley, V, Ayers, K, Koopman, P, Sinclair, A

Nat Commun 2018
22964823 Genetic control of testis development

Sekido, R, Lovell-Badge, R

Sex Dev 2013
30590466 Testis Development

Mäkelä, JA, Koskenniemi, JJ, Virtanen, HE, Toppari, J

Endocr. Rev. 2019
16046443 From SRY to SOX9: mammalian testis differentiation

Kanai, Y, Hiramatsu, R, Matoba, S, Kidokoro, T

J. Biochem. 2005
18445271 A GATA4/WT1 cooperation regulates transcription of genes required for mammalian sex determination and differentiation

Miyamoto, Y, Taniguchi, H, Hamel, F, Silversides, DW, Viger, RS

BMC Mol. Biol. 2008
11207191 Steroidogenic factor-1 contributes to the cyclic-adenosine monophosphate down-regulation of human SRY gene expression

De Santa Barbara, P, Méjean, C, Moniot, B, Malclès, MH, Berta, P, Boizet-Bonhoure, B

Biol. Reprod. 2001
9815658 The Wilms' tumor gene WT1 can regulate genes involved in sex determination and differentiation: SRY, Müllerian-inhibiting substance, and the androgen receptor

Shimamura, R, Fraizer, GC, Trapman, J, Lau, Y.C., Saunders, GF

Clin. Cancer Res. 1997
21412441 Failure of SOX9 regulation in 46XY disorders of sex development with SRY, SOX9 and SF1 mutations

Knower, KC, Kelly, S, Ludbrook, LM, Bagheri-Fam, S, Sim, H, Bernard, P, Sekido, R, Lovell-Badge, R, Harley, VR

PLoS ONE 2011
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