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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

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Project description:Environmental toxicants have been shown to induce the epigenetic transgenerational inheritance of adult onset disease, including testis disease and male infertility. The exposure of a gestating female during the period of gonadal sex determination has been shown to promote sperm epimutations, differential DNA methylation regions (DMR), that transmit transgenerational disease to subsequent generations. The current study was designed to determine the impact of an altered sperm epigenome on the subsequent development of an adult somatic cell (Sertoli cell) that influences the onset of a specific disease (male infertility). A gestating female rat (F0 generation) was exposed to the agriculture fungicide vinclozolin during gonadal sex determination and then the subsequent F3 generation progeny used for the isolation of Sertoli cells and assessment of testis disease. As previously observed, a spermatogenic cell apoptosis was observed. The Sertoli cells that provide the physical and nutritional support for the spermatogenic cells were isolated and alterations in gene expression examined. Over 400 genes were differentially expressed in the F3 generation control versus vinclozolin lineage Sertoli cells. A number of specific signaling pathways and cellular processes were identified to be transgenerationally altered. One of the key metabolic processes affected was pyruvate/lactate production that is directly linked to spermatogenic cell viability. The Sertoli cell epigenome was also altered with over 100 promoter differential DNA methylation regions (DMR) modified in the vinclozolin F3 generation Sertoli cell. The genomic features and overlap with the sperm DMR were investigated. Observations demonstrate that the transgenerational sperm epigenetic alterations subsequently alters the development of a specific somatic cell (Sertoli cell) epigenome and transcriptome that then has a role in the adult onset disease (male infertility). The environmentally induced epigenetic transgenerational inheritance of testis disease appears to be a component of the molecular etiology of male infertility. Environmental toxicants have been shown to induce the epigenetic transgenerational inheritance of adult onset male infertility. The exposure of a gestating female during the period of gonadal sex determination has been shown to promote sperm epimutations, differential DNA methylation regions (DMR), that transmit transgenerational disease to subsequent generations. The current study was designed to determine the impact of an altered sperm epigenome on the subsequent development of an adult somatic cell (Sertoli cell) that influences the onset of a specific disease (male infertility). A gestating female rat (F0 generation) was exposed to the agriculture fungicide vinclozolin during gonadal sex determination and then the subsequent F3 generation progeny used for the isolation of Sertoli cells and assessment of testis disease. The Sertoli cells provide the physical and nutritional support for the spermatogenic cells in the testis. The F3 generation Sertoli cells have an altered transcriptome and epigenome associated with adult onset testis disease. The environmentally induced epigenetic transgenerational inheritance of Sertoli cell abnormalities appears to be a component of the molecular etiology of male infertility. RNA samples from Sertoli cell of 3 F3-control lineage groups are compared to Sertoli cell of 3 F3-vinclozolin lineage groups

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

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