Perea-Gomez Aitana, Bellido Carreras Natividad, Dhellemmes Magali, Tang Furong, Le Gallo Coralie, Chaboissier Marie-Christine
Université Côte d'Azur, CNRS, INSERM, iBV, Nice, France.
Elife. 2025 Jul 10;14:RP103783. doi: 10.7554/eLife.103783.
Male genital development in XY mammalian fetuses is triggered by the action of hormones, including testosterone, secreted by the developing testes. Defects in this process are a cause for differences in sex development (DSD), one of the most common congenital abnormalities in humans. Fetal Leydig cells (FLCs) play a central role in the synthesis of masculinizing hormones in the developing testes. Yet, the genetic cascade controlling their differentiation is poorly understood. Here, we investigate the role of the orphan nuclear receptor NR2F2 (COUP-TFII) in FLC development. We report that NR2F2 is expressed in interstitial progenitor cells of the mouse embryonic testes and is downregulated upon their differentiation into FLC. By using two mouse models for conditional mutation of in the developing testes, we demonstrate that NR2F2 is required for testis morphogenesis and FLC development. NR2F2 acts in interstitial progenitors to regulate the initiation and progression of FLC differentiation. These results establish NR2F2 as an essential regulator of FLC development and steroid hormone synthesis in the mouse fetal testis and provide an entry point in understanding the etiology of 46,XY DSD associated with pathogenic NR2F2 variants.
XY 哺乳动物胎儿的雄性生殖器发育是由发育中的睾丸分泌的包括睾酮在内的激素作用所触发的。这一过程中的缺陷是性发育差异（DSD）的一个原因，DSD 是人类最常见的先天性异常之一。胎儿睾丸间质细胞（FLC）在发育中的睾丸中雄性化激素的合成中起核心作用。然而，控制其分化的基因级联反应却知之甚少。在这里，我们研究孤儿核受体 NR2F2（COUP-TFII）在 FLC 发育中的作用。我们报告称，NR2F2 在小鼠胚胎睾丸的间质祖细胞中表达，并且在它们分化为 FLC 时被下调。通过使用两种在发育中的睾丸中进行条件性突变的小鼠模型，我们证明 NR2F2 是睾丸形态发生和 FLC 发育所必需的。NR2F2 在间质祖细胞中起作用，以调节 FLC 分化的起始和进程。这些结果确立了 NR2F2 作为小鼠胎儿睾丸中 FLC 发育和类固醇激素合成的关键调节因子，并为理解与致病性 NR2F2 变体相关的 46,XY DSD 的病因提供了一个切入点。
