DMRT1, FOX and SOX

Following on from a previous post, from DMRT1 prevents female reprogramming in the postnatal mammalian testis by Marson et al, Nature (2011)

Sex in mammals is determined in the fetal gonad by the presence or absence of the Y chromosome gene Sry, which controls whether bipotential precursor cells differentiate into testicular Sertoli cells or ovarian granulosa cells [1]. This pivotal decision in a single gonadal cell type ultimately controls sexual differentiation throughout the body. Sex determination can be viewed as a battle for primacy in the fetal gonad between a male regulatory gene network in which Sry activates Sox9 and a female network involving WNT/β-catenin signalling [2]. In females the primary sex-determining decision is not final: loss of the FOXL2 transcription factor in adult granulosa cells can reprogram granulosa cells into Sertoli cells [2]. Here we show that sexual fate is also surprisingly labile in the testis: loss of the DMRT1 transcription factor [3] in mouse Sertoli cells, even in adults, activates Foxl2 and reprograms Sertoli cells into granulosa cells. In this environment, theca cells form, oestrogen is produced and germ cells appear feminized. Thus Dmrt1 is essential to maintain mammalian testis determination, and competing regulatory networks maintain gonadal sex long after the fetal choice between male and female. Dmrt1 and Foxl2 are conserved throughout vertebrates [4,5] and Dmrt1-related sexual regulators are conserved throughout metazoans [3]. Antagonism between Dmrt1 and Foxl2 for control of gonadal sex may therefore extend beyond mammals. Reprogramming due to loss of Dmrt1 also may help explain the aetiology of human syndromes linked to DMRT1, including disorders of sexual differentiation [6] and testicular cancer [7].

[1] Koopman, P., Gubbay, J., Vivian, N., Goodfellow, P. & Lovell-Badge, R. Male development of chromosomally female mice transgenic for Sry. Nature 351, 117–121 (1991)

[2] Uhlenhaut, N. H. et al. Somatic sex reprogramming of adult ovaries to testes by FOXL2 ablation. Cell 139, 1130–1142 (2009)

[3] Raymond, C. S. et al. Evidence for evolutionary conservation of sex-determining genes. Nature 391, 691–695 (1998)

[4] Loffler, K. A., Zarkower, D. & Koopman, P. 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 (2003)

[5] Raymond, C. S., Kettlewell, J. R., Hirsch, B., Bardwell, V. J. & Zarkower, D. Expression of Dmrt1 in the genital ridge of mouse and chicken embryos suggests a role in vertebrate sexual development. Dev. Biol. 215, 208–220 (1999)

[6] Tannour-Louet, M. et al. Identification of de novo copy number variants associated with human disorders of sexual development. PLoS ONE 5, e15392 (2010)

[7] Turnbull, C. et al. Variants near DMRT1, TERT and ATF7IP are associated with testicular germ cell cancer. Nature Genet. 42, 604–607 (2010)

This diagram from the body of the article might help explain what was done, and what the effects were. For more details, see the full article, available through library sibscription.



I have a personal interest in such matters of course. In my own case, 3BHDD is a really good explanation of everything except for the rapidity of the change. That remains unexplained. This may have something to do with it, or it might not. More data needed, though activation/deactivation of Foxl9/Sox2 seems likely to play a role. DMRT1? No idea, though I don't see how it could. We're still guessing, but every little bit of information helps. There's one case being looked at by the Mayo clinic - a more complete change than mine - where this genuinely might be the cause, even if it's not involved in my own case. Weird stuff happens.