Abstract
The male’s ability to reproduce is completely dependent on Sertoli cells. However, the mechanisms governing the functional integrity of Sertoli cells have remained largely unexplored. Here, we demonstrate that deletion of Shp2 in Sertoli cells results in infertility in mice. In Shp2 knockout mice (SCSKO), a normal population of Sertoli cells was observed, but the blood-testis barrier (BTB) was not formed. Shp2 ablation initiated the untimely and excessive differentiation of spermatogonial stem cells (SSCs) by disturbing the expression of paracrine factors. As a consequence, the process of spermatogenesis was disrupted, and the germ cells were depleted. Furthermore, Shp2 deletion impaired the cell junctions of the primary Sertoli cells and failed to support the clonal formation of SSCs co-cultured with SCSKO Sertoli cells. As expected, Shp2 restoration largely restores the cell junctions of the primary Sertoli cells and the clonal formation of SSCs. To identify the underlying mechanism, we further demonstrated that the absence of Shp2 suppressed Erk phosphorylation, and thus, the expression of follicle-stimulating hormone (FSH)- and testosterone-induced target genes. These results collectively suggest that Shp2 is a critical signaling protein that is required to maintain Sertoli cell function and could serve as a novel target for male infertility therapies.
Highlights
The male’s ability to reproduce is completely dependent on Sertoli cells
Shp[2] protein was clearly absent in Western blots of primary SCs, but not germ cells isolated from 14-day-old mice (Fig. 1B)
Adult SCSKO or littermate control male mice were mated with wild type female mice
Summary
Shp[2] in SCs and male reproduction, we generated Shp[2] conditional knockout mice using the loxp-cre system. The male knockout mice were infertile, and the testes were small and exhibited a damaged structure (Supplemental Fig. 2B and C). These results indicated that Shp[2] deficiency in SCs could injure testes development and induce male infertility in mice. At 4 weeks old, the seminiferous tubules in the Shp2f/f mice contained typical spermatogenic waves and elongated sperm (Fig. 2A, left, third image on the top panel), whereas most of the tubules (84%) in the SCSKO mice were obviously damaged and exhibited cell loss, vacuolization, a chaotic arrangement of germ cells, and the absence of elongated sperm (Fig. 2A, right, second image on the bottom panel, arrowhead indicated).
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