LRH1 can help reprogram sexual cell fate and is required for Sertoli cell development and spermatogonial stem cell maintenance in the mouse testis

ABSTRACT: The mammalian nuclear hormone receptors LRH1 and SF1 are close paralogs that can bind the same DNA site and play crucial roles in gonadal development and function. Lrh1 has been shown to be essential for follicle development in the ovary and also has been proposed to regulate steroidogenesis in the testis, but genetic analysis of its role in the male gonad has not been reported. Here we use conditional genetics to examine Lrh1 requirements in gonadal cell fate reprogramming and in normal development of the three major cell lineages of the mouse testis. Lrh1 expression is highly elevated by loss of the sex regulator Dmrt1, which triggers male-to-female transdifferentiation of Sertoli cells. We found that loss of Lrh1 suppresses this transdifferentiation, confirming that Lrh1 can act as a key driver in reprogramming sexual cell fate. In otherwise wild-type testes we found that Lrh1 is dispensable in Leydig cells but is required in Sertoli cells for their proliferation, for seminiferous tubule morphogenesis, for maintenance of the blood-testis barrier, for feedback regulation of androgen production, and for support of spermatogenesis. Expression profiling identified misexpressed genes likely underlying most aspects of the Sertoli cell phenotype. In the germ line Lrh1 is required for maintenance of spermatogonial stem cells (SSCs) and mutants progressively lose spermatogenesis. Reduced expression of the RNA binding factor Nxf2 likely contributes to the SSC maintenance defect. Unexpectedly, however, the Lrh1 mutant germ line can recover abundant spermatogenesis and fertility. This finding suggests the presence of a reserve stem cell population with different genetic requirements from the stem cells that normally support steady state spermatogenesis. Together our results demonstrate that Lrh1, like Sf1, is an essential regulator of testis development and function but has a distinct repertoire of functions.

ORGANISM(S): Mus musculus

PROVIDER: GSE180204 | GEO | 2022/02/10

REPOSITORIES: GEO