Foxl2 functions in sex determination and histogenesis throughout mouse ovary development.
Foxl2 functions in sex determination and histogenesis throughout mouse ovary development.
复制标题
DOI：
10.1186/1471-213x-9-36
复制
发表时间：
2009-06-18
影响因子：
--
通讯作者：
Ottolenghi C
中科院分区：
文献类型：
--
作者：
Garcia-Ortiz JE;Pelosi E;Omari S;Nedorezov T;Piao Y;Karmazin J;Uda M;Cao A;Cole SW;Forabosco A;Schlessinger D;Ottolenghi C
转录因子FOXL2功能的部分丧失导致女性卵巢早衰。在动物模型中，Foxl2是维持和可能诱导雌性性别决定所必需的，独立于其他关键基因，如Rspo1。在这里，我们报告了单独缺乏Foxl2或与Wnt4或Kit/c-Kit联合缺乏Foxl2的小鼠卵巢的表达谱。Foxl2缺失后，早期睾丸基因（包括Inhbb、Dhh和Sox9）和一些新的卵巢基因在胚胎发育过程中持续失调。在缺乏Foxl2的情况下，影响大部分途径的表达变化与在wnt4缺失的卵巢中观察到的相反，这加强了这些基因在卵巢发育中具有互补作用的概念。丢失一个Foxl2拷贝显示出强烈的基因剂量敏感性，分子异常轻微，但类似于缺乏两个Foxl2等位基因的卵巢。此外，Foxl2转基因破坏了胚胎睾丸的分化，增加了关键雌性标记的水平。综合主成分分析结果表明：1)Foxl2在卵巢分化过程中具有剂量依赖性的功能和抗睾丸作用；2)鉴定与FOXL2无关的性别决定相关的候选基因（如转录因子IRX3和ZBTB7C）和FOXL2下游卵巢储备的产生相关的候选基因（如钙粘蛋白结构域蛋白CLSTN2和鞘磷脂合成酶SGMS2）。基因清单是鉴定卵巢发育中部分自主作用的全部途径的第一步，从而为分析女性生育能力的遗传基础提供了一个框架。
Partial loss of function of the transcription factor FOXL2 leads to premature ovarian failure in women. In animal models, Foxl2 is required for maintenance, and possibly induction, of female sex determination independently of other critical genes, e.g., Rspo1. Here we report expression profiling of mouse ovaries that lack Foxl2 alone or in combination with Wnt4 or Kit/c-Kit. Following Foxl2 loss, early testis genes (including Inhbb, Dhh, and Sox9) and several novel ovarian genes were consistently dysregulated during embryonic development. In the absence of Foxl2, expression changes affecting a large fraction of pathways were opposite those observed in Wnt4-null ovaries, reinforcing the notion that these genes have complementary actions in ovary development. Loss of one copy of Foxl2 revealed strong gene dosage sensitivity, with molecular anomalies that were milder but resembled ovaries lacking both Foxl2 alleles. Furthermore, a Foxl2 transgene disrupted embryonic testis differentiation and increased the levels of key female markers. The results, including a comprehensive principal component analysis, 1) support the proposal of dose-dependent Foxl2 function and anti-testis action throughout ovary differentiation; and 2) identify candidate genes for roles in sex determination independent of FOXL2 (e.g., the transcription factors IRX3 and ZBTB7C) and in the generation of the ovarian reserve downstream of FOXL2 (e.g., the cadherin-domain protein CLSTN2 and the sphingomyelin synthase SGMS2). The gene inventory is a first step toward the identification of the full range of pathways with partly autonomous roles in ovary development, and thus provides a framework to analyze the genetic bases of female fertility.