Gonadal differentiation, sex determination and normal Sry expression in mice require direct interaction between transcription partners GATA4 and FOG2.
Gonadal differentiation, sex determination and normal Sry expression in mice require direct interaction between transcription partners GATA4 and FOG2.
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发表时间：
2002-10
期刊：
影响因子：
4.6
通讯作者：
S. Tevosian;K. H. Albrecht;J. Crispino;Y. Fujiwara;E. Eicher;S. Orkin
中科院分区：
文献类型：
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作者：
S. Tevosian;K. H. Albrecht;J. Crispino;Y. Fujiwara;E. Eicher;S. Orkin
在哺乳动物中，Sry在双能未分化性腺中的表达指导支持细胞前体分化为支持细胞，从而启动睾丸分化途径。在缺乏Sry的情况下，或者如果Sry表达水平不足，则支持细胞前体分化为颗粒细胞，从而启动卵巢途径。Sry上游和下游的分子机制还不清楚。我们证明，转录因子GATA 4和它的辅因子FOG 2所需的性腺分化。对于Fog 2的无效等位基因纯合的或对于Gata 4中的靶向突变（Gata 4（ki））纯合的小鼠胎儿表现出性腺发生的异常，所述靶向突变消除了GATA 4与FOG辅因子的相互作用。我们发现XY Fog 2（-/-）性腺中Sry转录水平在E11.5显著降低，E11.5是Sry表达正常达到峰值的时间。此外，正常支持细胞功能的三个关键基因（Sox 9，Mis和Dhh）和三个Leydig细胞类固醇生物合成酶（p450 SCC，3 β HSD和p450 c17）在XY Fog 2（-/-）和加塔（ki/ki）性腺中不表达，而Wnt 4，正常卵巢发育所需的基因，异位表达。相比之下，Wt 1和Sf 1，这是表达之前Sry和必要的性腺发育在两种性别，正常表达的两种类型的突变XY性腺。这些结果表明，GATA 4和FOG 2及其物理相互作用是正常性腺发育所必需的。
In mammals, Sry expression in the bipotential, undifferentiated gonad directs the support cell precursors to differentiate as Sertoli cells, thus initiating the testis differentiation pathway. In the absence of Sry, or if Sry is expressed at insufficient levels, the support cell precursors differentiate as granulosa cells, thus initiating the ovarian pathway. The molecular mechanisms upstream and downstream of Sry are not well understood. We demonstrate that the transcription factor GATA4 and its co-factor FOG2 are required for gonadal differentiation. Mouse fetuses homozygous for a null allele of Fog2 or homozygous for a targeted mutation in Gata4 (Gata4(ki)) that abrogates the interaction of GATA4 with FOG co-factors exhibit abnormalities in gonadogenesis. We found that Sry transcript levels were significantly reduced in XY Fog2(-/-) gonads at E11.5, which is the time when Sry expression normally reaches its peak. In addition, three genes crucial for normal Sertoli cell function (Sox9, Mis and Dhh) and three Leydig cell steroid biosynthetic enzymes (p450scc, 3betaHSD and p450c17) were not expressed in XY Fog2(-/-) and Gata(ki/ki) gonads, whereas Wnt4, a gene required for normal ovarian development, was expressed ectopically. By contrast, Wt1 and Sf1, which are expressed prior to Sry and necessary for gonad development in both sexes, were expressed normally in both types of mutant XY gonads. These results indicate that GATA4 and FOG2 and their physical interaction are required for normal gonadal development.