OIP5 Interacts with NCK2 to Mediate Human Spermatogonial Stem Cell Self-Renewal and Apoptosis through Cell Cyclins and Cycle Progression and Its Abnormality Is Correlated with Male Infertility  

作　　者：Yinghong Cui Wei Chen Li Du Zuping He 

机构地区：[1]The Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province,The Research Center of Reproduction and Translational Medicine of Hunan Province,Hunan Normal University School of Medicine,Changsha 410013,Hunan,China

出　　处：《Research》2024年第1期455-469,共15页研究（英文）

基　　金：the grants from the National Nature Science Foundation of China(32170862 and 31872845);Major Scientific and Technological Projects for Collaborative Prevention and Control of Birth Defect in Hunan Province(2019SK1012);Key Grant of Research and Development in Hunan Province(2020DK2002);Developmental Biology and Breeding(2022XKQ0205);Natural Science Foundation of Hunan Province of China(2020JJ5380,2020JJ5383,and 2021JJ40365);a grant from the Shanghai Key Laboratory of Reproductive Medicine.

摘　　要：Spermatogonial stem cells(SSCs)have important applications in both reproduction and regenerative medicine.Nevertheless,specific genes and signaling transduction pathways in mediating fate decisions of human SSCs remain elusive.Here,we have demonstrated for the first time that OIP5(Opa interacting protein 5)controlled the self-renewal and apoptosis of human SSCs.RNA sequencing identified that NCK2 was a target for OIP5 in human SSCs,and interestingly,OIP5 could interact with NCK2 as shown by Co-IP(co-immunoprecipitation),IP-MS(mass spectrometry),and GST pulldown assays.NCK2 silencing decreased human SSC proliferation and DNA synthesis but enhanced their apoptosis.Notably,NCK2 knockdown reversed the influence of OIP5 overexpression on human SSCs.Moreover,OIP5 inhibition decreased the numbers of human SSCs at S and G2/M phases,while the levels of numerous cell cycle proteins,including cyclins A2,B1,D1,E1 and H,especially cyclin D1,were remarkably reduced.Significantly,whole-exome sequencing of 777 patients with nonobstructive azoospermia(NOA)revealed 54 singlenucleotide polymorphism mutations of the OIP5 gene(6.95%),while the level of OIP5 protein was obviously lower in testes of NOA patients compared to fertile men.Collectively,these results implicate that OIP5 interacts with NCK2 to modulate human SSC self-renewal and apoptosis via cell cyclins and cell cycle progression and that its mutation and/or lower expression is correlated with azoospermia.As such,this study offers novel insights into molecular mechanisms underlying the fate determinations of human SSCs and the pathogenesis of NOA,and it provides new targets for treating male infertility.

关 键 词：OIP5 APOPTOSIS reversed 

分 类 号：R329.2[医药卫生—人体解剖和组织胚胎学]