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Abstract

Volume 22, Issue 4 (July 2020) 22, 414–421; 10.4103/aja.aja_76_19

Mkrn2 deficiency induces teratozoospermia and male infertility through p53/PERP-mediated apoptosis in testis

Ying-Chen Qian1, Yun-Xia Xie1, Chao-Shan Wang1, Zhu-Mei Shi2, Cheng-Fei Jiang1, Yun-Yi Tang1, Xu Qian1, Lin Wang3, Bing-Hua Jiang1,3,4

1 Department of Pathology, Nanjing Medical University, Nanjing 210029, China
2 Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
3 The Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450001, China
4 Department of Pathology, The University of Iowa, Iowa City, IA 52242, USA

Correspondence: Dr. BH Jiang (binghjiang@yahoo.com)

Date of Submission 11-Nov-2018 Date of Acceptance 13-Jun-2019 Date of Web Publication 06-Sep-2019

Abstract

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.

Keywords: apoptosis; makorin-2; p53; p53 apoptosis effector related to PMP22; spermatogenesis

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