Dataset Information

OSR1 and SPAK cooperatively modulate Sertoli cell support of mouse spermatogenesis.

ABSTRACT: We investigated the role of oxidative stress-responsive kinase-1 (OSR1) and STE20 (sterile 20)/SPS1-related proline/alanine-rich kinase (SPAK), upstream regulators of the Na⁺-K⁺-2Cl^- cotransporter (NKCC1)-essential for spermatogenesis-in mouse models of male fertility. Global OSR1^+/- gene mutations, but not global SPAK^-/- or Sertoli cell (SC)-specific OSR1 gene knockout (SC-OSR1^-/-), cause subfertility with impaired sperm function and are associated with reduced abundance of phosphorylated (p)-NKCC1 but increased p-SPAK expression in testicular tissue and spermatozoa. To dissect further in a SC-specific manner the compensatory effect of OSR1 and SPAK in male fertility, we generated SC-OSR1^-/- and SPAK^-/- double knockout (DKO) male mice. These are infertile with defective spermatogenesis, presenting a SC-only-like syndrome. Disrupted meiotic progression and increased germ cell apoptosis occurred in the first wave of spermatogenesis. The abundance of total and p-NKCC1 was significantly decreased in the testicular tissues of DKO mice. These results indicate that OSR1 and SPAK cooperatively regulate NKCC1-dependent spermatogenesis in a SC-restricted manner.

SUBMITTER: Liu YL

PROVIDER: S-EPMC5112561 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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OSR1 and SPAK cooperatively modulate Sertoli cell support of mouse spermatogenesis.

Liu Yung-Liang YL Yang Sung-Sen SS Chen Shyi-Jou SJ Lin Yu-Chun YC Chu Chin-Chen CC Huang Hsin-Hui HH Chang Fung-Wei FW Yu Mu-Hsien MH Lin Shih-Hua SH Wu Gwo-Jang GJ Sytwu Huey-Kang HK

Scientific reports 20161117

We investigated the role of oxidative stress-responsive kinase-1 (OSR1) and STE20 (sterile 20)/SPS1-related proline/alanine-rich kinase (SPAK), upstream regulators of the Na+-K+-2Cl- cotransporter (NKCC1)-essential for spermatogenesis-in mouse models of male fertility. Global OSR1+/- gene mutations, but not global SPAK-/- or Sertoli cell (SC)-specific OSR1 gene knockout (SC-OSR1-/-), cause subfertility with impaired sperm function ...[more]

PMID: 27853306

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Project description: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.

Dataset Information

OSR1 and SPAK cooperatively modulate Sertoli cell support of mouse spermatogenesis.

Publications

OSR1 and SPAK cooperatively modulate Sertoli cell support of mouse spermatogenesis.

Similar Datasets

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