Université Côte d'Azur, CNRS, Inserm, Institut de Biologie Valrose (iBV), 06108 Nice, France.
Cells. 2020 Apr 29;9(5):1103. doi: 10.3390/cells9051103.
The transcription factors SRY and SOX9 and RSPO1/WNT4/β-Catenin signaling act as antagonistic pathways to drive testis and ovary development respectively, from a common gonadal primordium in mouse embryos. In this work, we took advantage of a double knockout mouse model to study gonadal development when and are both mutated. We show that the XX gonad mutant for or for both and develop as ovotestes, demonstrating that ectopic SOX9 function is not required for the partial female-to-male sex reversal caused by a mutation. deletion in XY gonads leads to ovarian development accompanied by ectopic WNT/β-catenin signaling. In XY mutant gonads, SRY-positive supporting precursors adopt a female-like identity and develop as pre-granulosa-like cells. This phenotype cannot be fully prevented by the deletion of or , indicating that SOX9 is required for the early determination of the male supporting cell identity independently of repressing RSPO1/WNT4/β-Catenin signaling. However, in XY double mutant gonads, pre-granulosa cells are not maintained, as they prematurely differentiate as mature granulosa cells and then trans-differentiate into Sertoli-like cells. Together, our results reveal the dynamics of the specific and independent actions of SOX9 and WNT4 during gonadal differentiation: SOX9 is essential in the testis for early specification of male-supporting cells whereas WNT4 functions in the ovary to maintain female-supporting cell identity and inhibit male-specific vascular and steroidogenic cell differentiation.
转录因子 SRY 和 SOX9 以及 RSPO1/WNT4/β-连环蛋白信号通路作为拮抗途径，分别从小鼠胚胎的共同性腺原基中驱动睾丸和卵巢的发育。在这项工作中，我们利用双敲除小鼠模型研究了 和 同时突变时的性腺发育。我们发现 XX 性腺突变体对于 或 和 都是缺失的，都发育为卵睾，表明 SOX9 异位功能对于由 突变引起的部分雌性到雄性的性别反转不是必需的。XY 性腺中 的缺失导致卵巢发育伴随着异位 WNT/β-连环蛋白信号。在 XY 突变体性腺中，SRY 阳性支持前体细胞采用女性样特征并发育为类似于原始颗粒细胞样细胞。这种表型不能完全被 或 的缺失所预防，表明 SOX9 独立于抑制 RSPO1/WNT4/β-连环蛋白信号，对于雄性支持细胞身份的早期决定是必需的。然而，在 XY 双突变体性腺中，原始颗粒细胞不能维持，因为它们过早分化为成熟颗粒细胞，然后转分化为 Sertoli 样细胞。总之，我们的结果揭示了 SOX9 和 WNT4 在性腺分化过程中的特异性和独立性作用的动态：SOX9 在睾丸中对于雄性支持细胞的早期特化是必需的，而 WNT4 在卵巢中维持雌性支持细胞身份并抑制雄性特异性血管和类固醇生成细胞分化。
