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Genes Involved in Formation of the Bipotent Gonad

المؤلف:  Wass, J. A. H., Arlt, W., & Semple, R. K. (Eds.).

المصدر:  Oxford Textbook of Endocrinology and Diabetes

الجزء والصفحة:  3rd edition , p1160-1161

2026-10-05

102

Studies of knock out mice and people with gonadal dysgenesis provided information on genes involved in genital ridge development. A set of genes including GATA binding protein 4 (Gata4), nuclear receptor subfamily 5 group A member 1 (Nr5a1, also known as steroidogenic factor 1, Sf1), Wilms tumour 1 (Wt1), Lim homeobox protein 9 (Lhx9) and empty spiracles homeobox 2 (Emx2) have all been shown to be vital to the development of the genital ridge. Wt1 is expressed as early as 9.5 dpc in the whole urogenital ridge and plays an important role in the development of the gonad as well as the kidneys. This zinc finger transcription factor has 24 isoforms. Alternative splicing leads to an insertion or omission of three amino acids (+/ – KTS; lysine, threonine, serine) between the third and fourth zinc finger. The Wt1- KTS isoform seems to have a key role in gonadal ridge development since ablation of the Wt1- KTS leads to a lack of broadening of the genital ridge due to in creased apoptosis.

GATA4 is a zinc finger transcription factor that is necessary for genital ridge initiation and is expressed in the genital ridge in an anterior- posterior direction preceding immediately the thickening of the coelomic epithelium. Gata4 knock- out is embryonic lethal due to defects in early ventral morphogenesis. Therefore, conditional Gata4 knock- out mice have been created that display no gonadal initiation. Their coelomic epithelium remains a monolayer and the basement membrane underneath persists unfragmented preventing migration. Knock out mice for Emx2 also show gonadal dysgenesis and a decrease of epithelial cells migrating to the mesenchymal part of the gonadal ridge. In humans, haploinsufficiency caused by deletions encompassing EMX2 have been linked to a wide spectrum of DSD ranging from hypospadias to complete sex reversal. Lhx9 KO mice show agenesis of the gonads in both sexes. The genital ridge develops, but the coelomic epithelium fails to proliferate and gonads are not formed. Nevertheless, germ cells migrate normally to the presumptive gonadal region at the expected time. Although mice lacking Lhx9 do not exhibit further severe defects, to date no mutations in this gene in humans have been described. Nr5a1 expression follows Gata4 expression and is restricted to the genital ridge and the ad renal primordium. Mice lacking Nr5a1 have a similar phenotype to Lhx9 KO mice. They lack adrenal glands and gonads and both male and female mice have female internal genitalia. Interestingly, expression of Nr5a1 in Lhx9 – / – mice is greatly reduced, suggesting that LHX9 might be a regulator acting upstream of Nr5a1.

After fragmentation of the basement membrane some proliferating SF1 positive cells of the coelomic epithelium undergo epithelial- mesenchymal transformation (EMT) and migrate inwards into the mesenchyme forming the gonadal somatic precursor cells.