Open AccessMkrn2 deficiency induces teratozoospermia and male infertility through p53/PERP-mediated apoptosis in testis
Author(s) -
Ying-Chen Qian,
Yaoqin Xie,
Chaoshan Wang,
Zhumei Shi,
Cuiping Jiang,
Yunyi Tang,
Xu Qian,
Lin Wang,
BingHua Jiang
Publication year - 2020
Publication title -
asian journal of andrology/asian journal of andrology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.701
H-Index - 74
eISSN - 1745-7262
pISSN - 1008-682X
DOI - 10.4103/aja.aja_76_19
Subject(s) - biology , male infertility , spermatogenesis , apoptosis , kegg , gene , infertility , andrology , gene expression profiling , sperm , germ cell , gene expression , ectopic expression , genetics , endocrinology , transcriptome , medicine , pregnancy
The apoptosis that occurs in the immature testis under physiological conditions is necessary for male germ cell development, whereas improper activation of apoptosis can impair spermatogenesis and cause defects in reproduction. We previously demonstrated that in mice, the makorin-2 (Mkrn 2) gene is expressed exclusively in the testis and its deletion leads to male infertility. To understand the potential molecular mechanism, in this study, we found that levels of apoptosis in the testis were abnormally high in the absence of Mkrn 2. To identify specific gene(s) involved, we performed digital gene expression profiling (DGE) and pathway analysis via gene set enrichment analysis (GSEA) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, and we found that MKRN2 inhibits p53 apoptosis effector related to PMP22 (PERP) expression and that levels of the protein in sperm samples have an inverse correlation with infertility levels. GSEA additionally indicated that PERP is a negative regulator of spermatogenesis and that its ectopic expression induces male infertility. Further, Gene Expression Omnibus (GEO) dataset analysis showed that p53, upstream of PERP, was upregulated in oligoasthenoteratozoospermia (OAT). These observations suggest that Mkrn 2 is crucial for protecting germ cells from excessive apoptosis and implicate Mkrn 2-based suppression of the p53/PERP signaling pathway in spermatogenesis and male fertility.