Manuylov Nikolay L, Fujiwara Yuko, Adameyko Igor I, Poulat Francis, Tevosian Sergei G
Department of Genetics, Dartmouth Medical School, Hanover, NH, USA.
Dev Biol. 2007 Jul 15;307(2):356-67. doi: 10.1016/j.ydbio.2007.04.040. Epub 2007 May 3.
We have previously established an in vivo requirement for GATA4 and FOG2 transcription factors in sexual differentiation. Fog2 null mouse fetuses or fetuses homozygous for a targeted mutation in Gata4 (Gata4(ki)), which cripples the GATA4-FOG2 interaction, exhibit a profound and early block in testis differentiation in both sexes. Others have shown that XX mice with the Ods transgenic insertion or the Wt1-Sox9 YAC transgene overexpress the testis differentiation gene, Sox9. Thus, these XX animals undergo dominant sex reversal by developing into phenotypically normal, but sterile, males. Now we have determined that Fog2 haploinsufficiency prevents (suppresses) this dominant sex reversal and Fog2+/-Wt1-Sox9 or Ods XX animals develop normally--as fertile females. The suppression of sex reversal in Fog2 heterozygous females results from approximately 50% downregulation of the expression from the transgene-associated allele of Sox9. The GATA4/FOG2-dependent sex reversal observed in the transgenic XX gonads has to rely on gene targets other than the Y chromosome-linked Sry gene. Importantly, Fog2 null or Gata4(ki/ki) embryos (either XX or XY) fail to express detectable levels of Sox9 despite carrying the Ods mutation or Wt1-Sox9 transgene. Fog2 haploinsufficiency leads to a decreased amount of SOX9-positive cells in XY gonads. We conclude that FOG2 is a limiting factor in the formation of a functional GATA4/FOG2 transcription complex that is required for Sox9 expression during gonadogenesis.
我们之前已经确定了GATA4和FOG2转录因子在性别分化过程中的体内需求。Fog2基因敲除的小鼠胎儿或Gata4基因发生靶向突变（Gata4(ki)）的纯合子胎儿，其GATA4-FOG2相互作用受损，在两性中均表现出睾丸分化的严重早期阻滞。其他人已经表明，携带Ods转基因插入或Wt1-Sox9 YAC转基因的XX小鼠会过度表达睾丸分化基因Sox9。因此，这些XX动物通过发育成表型正常但不育的雄性而发生显性性反转。现在我们已经确定，Fog2单倍体不足可阻止（抑制）这种显性性反转，并且Fog2+/-Wt1-Sox9或Ods XX动物正常发育——成为可育雌性。Fog2杂合雌性中性别反转的抑制是由于Sox9转基因相关等位基因的表达下调了约50%。在转基因XX性腺中观察到的GATA4/FOG2依赖性性别反转必须依赖于Y染色体连锁的Sry基因以外的基因靶点。重要的是，尽管携带Ods突变或Wt1-Sox9转基因，Fog2基因敲除或Gata4(ki/ki)胚胎（XX或XY）均无法表达可检测水平的Sox9。Fog2单倍体不足导致XY性腺中SOX9阳性细胞数量减少。我们得出结论，FOG2是功能性GATA4/FOG2转录复合物形成过程中的一个限制因素，而该复合物是性腺发生过程中Sox9表达所必需的。
