Nachtigal M W, Hirokawa Y, Enyeart-VanHouten D L, Flanagan J N, Hammer G D, Ingraham H A
Department of Physiology, University of California at San Francisco, 94143-0444, USA.
Cell. 1998 May 1;93(3):445-54. doi: 10.1016/s0092-8674(00)81172-1.
Products of steroidogenic factor 1 (SF-1) and Wilms' tumor 1 (WT1) genes are essential for mammalian gonadogenesis prior to sexual differentiation. In males, SF-1 participates in sexual development by regulating expression of the polypeptide hormone Müllerian inhibiting substance (MIS). Here, we show that WT1 -KTS isoforms associate and synergize with SF-1 to promote MIS expression. In contrast, WT1 missense mutations, associated with male pseudohermaphroditism in Denys-Drash syndrome, fail to synergize with SF-1. Additionally, the X-linked, candidate dosage-sensitive sex-reversal gene, Dax-1, antagonizes synergy between SF-1 and WT1, most likely through a direct interaction with SF-1. We propose that WT1 and Dax-1 functionally oppose each other in testis development by modulating SF-1-mediated transactivation.
在性别分化之前，类固醇生成因子1（SF-1）和威尔姆斯瘤1（WT1）基因的产物对于哺乳动物性腺发育至关重要。在雄性中，SF-1通过调节多肽激素苗勒氏管抑制物质（MIS）的表达参与性发育。在此，我们表明WT1 -KTS亚型与SF-1相互关联并协同作用以促进MIS表达。相比之下，与迪尼-德拉斯综合征中的男性假两性畸形相关的WT1错义突变无法与SF-1协同作用。此外，X连锁的候选剂量敏感性性反转基因Dax-1拮抗SF-1与WT1之间的协同作用，最有可能是通过与SF-1的直接相互作用。我们提出，WT1和Dax-1在睾丸发育中通过调节SF-1介导的反式激活在功能上相互对立。
