Sex Determination and the SRY Gene
Ryohei Sekido & Robin Lovell-Badge. 2008. Sex determination involves synergistic action of SRY and SF1 on a specific Sox9 enhancer. Nature 453: 930-934.
N. Henriette Uhlenhaut et.al, Robin Lovell-Badge, Mathias Treier. 2009.
Somatic Sex Reprogramming of Adult Ovaries to Testes by FOXL2 Ablation. Cell 139:6 1130-42.
Briefly tell us a bit about yourself, your career path over the years, and specifically what brought you to begin working on mammalian Sex Determination and your famous discovery of the SRY gene.
Michael J. F. Barresi
What initiates the burst of SRY expression that sets off the gene regulatory network leading to testes development?
FOXl2 and SOX9 are described as the “ying and yang of sex maintenance” where one would tip the scale to determine the sex. Is it possible for a situation to occur in which both would be expressed in exactly equal amounts? If so, what type of gonad (male or female) would be produced?
In “Sex determination involves synergistic action of SRY and SF1 on a specific Sox9 enhancer,” it states that “Transgenic mice with SRYmut or SF1mut showed enhancer activities similar to that of the wild-type sequence, whereas those with BOTH mut showed none at all, except for one with very weak expression” (pg. 931). If I understand correctly, this would indicate that when all SRY and SF1 sites were mutated, there was still expression of TESCO in one instance; thus, suggesting that SRY and SF1 are not completely required to activate it synergistically. Do you agree? Alternatively, how would you explain this result and what it means for the expression of Sox9?
Would the addition of Foxl2 repress Sox9 expression in adult XY males leading to similar transdifferentiation as the one seen in females? How feasible would this be from a male differentiation standpoint? Is the maintenance of testes similar to that of ovaries or is the fate of testes determined upon differentiation?
After I read these papers, I found it is extremely interesting that sex determination depends on continuous competition of genes and proteins to maintain ovarian or testis development. Changing a gene can result in sex transversal and sex reprogramming in adult. Why do the gonad cells retain this “versatile” ability rather than have a more determined fate like other differentiated cells? What is the evolutional advantage for this?
You ruled out the possibility that Tamoxifen administration did not influence the sex reversed phenotype. You also verified the role the ESR1 plays in derepression of the TESCO element. How is it possible that the antagonistic estrogen activity of tamoxifen did not have an obvious effect on ESR1 function in the FOXL2f/f control ovaries?
Yvanka De Soysa
How do you think your results could influence the development of treatments for children with disorders of sexual development and women experiencing premature menopause?
Zarnab Iftikhar, read by Hannah Beatty