Abstract
The mammalian nuclear hormone receptors LRH1 (NR5A2) and SF1 (NR5A1) are close paralogs that can bind the same DNA motif and play crucial roles in gonadal development and function. Lrh1 is essential for follicle development in the ovary and has been proposed to regulate steroidogenesis in the testis. Lrh1 expression in the testis is highly elevated by loss of the sex regulator Dmrt1, which triggers male-to-female transdifferentiation of Sertoli cells. While Sf1 has a well-defined and crucial role in testis development, no function for Lrh1 in the male gonad has been reported. Here we use conditional genetics to examine Lrh1 requirements both in gonadal cell fate reprogramming and in normal development of the three major cell lineages of the mouse testis. We find that loss of Lrh1 suppresses sexual transdifferentiation, confirming that Lrh1 can act as a key driver in reprogramming sexual cell fate. In otherwise wild-type testes, we find 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 we found that Lrh1 is required for maintenance of functional spermatogonia, and hence mutants progressively lose spermatogenesis. Reduced expression of the RNA binding factor Nxf2 likely contributes to the SSC defect. Unexpectedly, however, over time the Lrh1 mutant germ line recovered abundant spermatogenesis and fertility. This finding indicates that severe germ line depletion triggers a response allowing mutant spermatogonia to recover the ability to undergo complete spermatogenesis. Our results demonstrate that Lrh1, like Sf1, is an essential regulator of testis development and function but has a very distinct repertoire of functions.
Highlights
Formation of the mammalian gonad requires the coalescence of migrating primordial germ cells with somatic progenitor cells during fetal development, followed by complex and sexually dimorphic growth and differentiation programs that give rise to either male testes or female ovaries [1]
We found that Liver receptor homolog 1 (Lrh1) is essential for establishment and function of Sertoli cells, which provide support for germ cell development
We found that Lrh1 is required in the germ cells themselves to maintain functional stem cells that allow males to produce vast quantities of sperm throughout adult life
Summary
Formation of the mammalian gonad requires the coalescence of migrating primordial germ cells with somatic progenitor cells during fetal development, followed by complex and sexually dimorphic growth and differentiation programs that give rise to either male testes or female ovaries [1]. In both sexes the gonads play dual roles: they produce sex hormones and other signaling molecules that direct and support sexual differentiation and reproduction; and they produce gametes, either sperm or oocytes, that perpetuate the genome. Loss of SSC regulators can result in a gradual depletion of SSCs, and of spermatogenesis, due to reduced self-renewal, proliferation, or both [6,7,8]
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