The human and mouse sex-determining SRY genes repress the Rspo1/β-catenin signaling

被引:42
|
作者
Lau, Yun-Fai Chris [1 ]
Li, Yunmin [1 ]
机构
[1] Univ Calif San Francisco, VA Med Ctr, Dept Med, Div Cell & Dev Genet, San Francisco, CA 94121 USA
关键词
SRY; sex determination; R-spondin; 1; canonical Wnt signaling; beta-catenin; protein interaction; APICAL ECTODERMAL RIDGE; BETA-CATENIN; R-SPONDIN; GONADAL DEVELOPMENT; R-SPONDIN1; EXPRESSION; TRANSCRIPTION; SOX9; WNT4; DIFFERENTIATION;
D O I
10.1016/S1673-8527(08)60107-1
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 Sty 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 Sty 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 Sty 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.
引用
收藏
页码:193 / 202
页数:10
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