Lau Yun-Fai Chris, Li Yunmin
Division of Cell and Developmental Genetics, Department of Medicine, VA Medical Center, University of California, San Francisco, CA 94121, USA.
J Genet Genomics. 2009 Apr;36(4):193-202. doi: 10.1016/S1673-8527(08)60107-1.
The sex-determining region Y (SRY) is the gene on the Y chromosome responsible for switching on male sex determination during mammalian embryogenesis. In its absence, ovaries develop in the embryo. Hence, ovarian determination and differentiation is considered to be a default, or passive, developmental pathway. Recently this classical paradigm of sex determination has been challenged with the discovery of the R-spondin 1 (RSPO1) as an active ovarian determinant. Mutations of RSPO1 cause a female-to-male sex reversal. RSPO1 synergizes with WNT4 in activating an ovarian development in the bipotential gonad via the canonical Wnt signaling. Early studies showed that SRY represses such Wnt signaling, but also generated discrepancies on whether only mouse Sry is capable of inhibiting such Wnt signaling and whether both human and mouse SRY proteins are able to interact with beta-catenin, the intracellular messenger responsible for executing the Wnt signals. Our studies show that both human SRY and mouse Sry are capable of repressing the Rspo1/Wnt/beta-catenin signaling. However, the repression activities vary among different SRY/Sry proteins and paradoxically related to the presence and/or size of an acidic/glutamine-rich domain. The HMG box of human SRY could bind directly to beta-catenin while the mouse Sry binds to beta-catenin via its HMG box and glutamine-rich domain. The results clarify some of the initial discrepancies, and raise the possibility that SRY interacts with beta-catenin in the nucleus and represses the transcriptional activation of the Rspo1/Wnt target genes involved in ovarian determination, thereby switching on testis determination.
Y染色体性别决定区（SRY）是Y染色体上的一个基因，负责在哺乳动物胚胎发育过程中启动雄性性别决定。在缺乏该基因的情况下，胚胎会发育出卵巢。因此，卵巢的决定和分化被认为是一种默认的或被动的发育途径。最近，随着R-spondin 1（RSPO1）作为一种活跃的卵巢决定因子的发现，这一经典的性别决定范式受到了挑战。RSPO1的突变会导致女性向男性的性反转。RSPO1与WNT4协同作用，通过经典的Wnt信号通路激活双潜能性腺中的卵巢发育。早期研究表明，SRY会抑制这种Wnt信号通路，但在只有小鼠Sry能够抑制这种Wnt信号通路以及人类和小鼠SRY蛋白是否都能与β-连环蛋白（负责执行Wnt信号的细胞内信使）相互作用方面也产生了分歧。我们的研究表明，人类SRY和小鼠Sry都能够抑制Rspo1/Wnt/β-连环蛋白信号通路。然而，不同的SRY/Sry蛋白的抑制活性有所不同，而且矛盾的是，这与一个富含酸性/谷氨酰胺的结构域的存在和/或大小有关。人类SRY的HMG框可以直接与β-连环蛋白结合，而小鼠Sry则通过其HMG框和富含谷氨酰胺的结构域与β-连环蛋白结合。这些结果澄清了一些最初的分歧，并提出了SRY在细胞核中与β-连环蛋白相互作用并抑制参与卵巢决定的Rspo1/Wnt靶基因的转录激活从而启动睾丸决定的可能性。
