Abstract
SummaryDevelopment of spermatogonia and spermatocytes are the critical steps of spermatogenesis, impacting on male fertility. Investigation of the related regulators benefits the understanding of male reproduction. The proteasome system has been reported to regulate spermatogenesis, but the mechanisms and key contributing factors in vivo are poorly explored. Here we found that ablation of REGγ, a proteasome activator, resulted in male subfertility. Analysis of the mouse testes after birth showed there was a decreased number of PLZF+ spermatogonia and spermatocytes. Molecular analysis found that REGγ loss significantly increased the abundance of p53 protein in the testis, and directly repressed PLZF transcription in cell lines. Of note, allelic p53 haplodeficiency partially rescued the defects in spermatogenesis observed in REGγ-deficient mice. In summary, our results identify REGγ-p53-PLZF to be a critical pathway that regulates spermatogenesis and establishes a new molecular link between the proteasome system and male reproduction.
Highlights
Spermatogenesis is a highly complex and organized process of sperm cell development (Walker, 2009)
We found that REGg knockout reduced male mouse fertility, with mice exhibiting defects in spermatogenesis
Our results identify REGg as a critical factor required for normal PLZF-expressing spermatogonial stem cell representation and spermatogenesis, partially by regulation of the p53-PLZF pathway
Summary
Spermatogenesis is a highly complex and organized process of sperm cell development (Walker, 2009) It can broadly be categorized into three stages: the mitotic proliferation of spermatogonia, the meiotic division into haploid germ cells, and spermiogenic differentiation (Zhou et al, 2016). Spermatogonial stem cells (SSCs) are critical for this whole process (Walker, 2009; Wang et al, 2016; Xu et al, 2017; Zhang et al, 2016; Zhou et al, 2016) These SSCs undergo both selfrenewal and differentiating divisions and serve as the precursors to spermatozoa (Lovasco et al, 2015). Some transcription factors, such as PLZF, P53, Bcl6b, Lhx, Etv, and Id4, have been reported to regulate SSC self-renewal and proliferation (Beumer et al, 1998; Helsel et al, 2017; Kubota et al, 2004; La et al, 2018; Oatley et al, 2006)
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