Abstract:
To investigate the role of the nuclear receptor NR5A1 in the testis after sex determination, we analyzed mice lacking NR5A1 in Sertoli cells (SCs) from embryonic day (E) 13.5 onwards. Ablation of Nr5a1 impaired the expression of genes characteristic of SC identity (e.g. Sox9 and Amh), caused SC death from E14.5 onwards through a Trp53-independent mechanism related to anoikis, and induced disorganization of the testis cords. Together, these effects caused germ cells to enter meiosis and die. Single-cell RNA-sequencing experiments revealed that NR5A1-deficient SCs changed their molecular identity: some acquired a \'pre-granulosa-like\' cell identity, whereas other reverted to a \'supporting progenitor-like\' cell identity, most of them being \'intersex\' because they expressed both testicular and ovarian genes. Fetal Leydig cells (LCs) did not display significant changes, indicating that SCs are not required beyond E14.5 for their emergence or maintenance. In contrast, adult LCs were absent from postnatal testes. In addition, adult mutant males displayed persistence of Müllerian duct derivatives, decreased anogenital distance and reduced penis length, which could be explained by the loss of AMH and testosterone synthesis due to SC failure.
摘要:
探讨核受体NR5A1在睾丸性别决定后的作用,我们分析了从胚胎第(E)13.5天开始的支持细胞(SCs)中缺乏NR5A1的小鼠.Nr5a1的消融损害了SC同一性特征性基因(例如Sox9和Amh)的表达,从E14.5开始,通过与失巢凋亡相关的Trp53独立机制导致SC死亡,并诱发睾丸索的解体。一起,这些影响导致生殖细胞进入减数分裂并死亡。单细胞RNA测序实验显示,NR5A1缺陷的SCs改变了它们的分子身份:一些获得了“前颗粒样”细胞身份,而其他人恢复到“支持祖细胞样”的细胞身份,他们中的大多数是“双性人”,因为他们同时表达睾丸和卵巢基因。胎儿Leydig细胞(LCs)没有显示出显著的变化,表明SCs的出现或维持不需要超过E14.5。相比之下,成年LCs在出生后的睾丸中缺失。此外,成年突变雄性显示出苗勒管衍生物的持久性,肛门生殖器距离减少,阴茎长度减少,这可以解释为由于SC失败导致的AMH和睾酮合成的损失。