NEK2 Contributes to the Protection Against Cryptorchidism Outcomes

IF 1.6 4区医学 Q4 DEVELOPMENTAL BIOLOGY

Birth Defects Research Pub Date : 2025-05-19 DOI:10.1002/bdr2.2485

Xiaomeng Zhou, Songyi Ye, Xuehan Wang, Zhirong Liang, Neng Qian, Linghua Ji, Hua Xian, Ziheng Wang, Wenliang Ge

{"title":"NEK2 Contributes to the Protection Against Cryptorchidism Outcomes","authors":"Xiaomeng Zhou, Songyi Ye, Xuehan Wang, Zhirong Liang, Neng Qian, Linghua Ji, Hua Xian, Ziheng Wang, Wenliang Ge","doi":"10.1002/bdr2.2485","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Background</h3>\n \n <p>Cryptorchidism, characterized by the failure of testicular descent, is a common congenital disorder adversely affecting male reproductive health. Intriguingly, the NIMA-related kinase 2 (<i>NEK2</i>) gene has been implicated in various cellular processes, but its role in cryptorchidism remains underexplored.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>To elucidate NEK2's role, the researchers utilized NEK2 knockout mice, analyzing testes histology with hematoxylin–eosin (HE) staining and assessing sperm morphology by Diff-Quick staining. Immunohistofluorescence evaluated Leydig cell count, while Western blotting and immunohistochemistry analyzed 3β-hydroxysteroid dehydrogenase 1 (HSD3B1), critical for testosterone synthesis. Mouse testosterone levels were quantified by ELISA, and RT-qPCR examined testicular Wnt–β-catenin and HIPPO pathway expression.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>NEK2-deficient mice exhibited significantly increased cryptorchidism incidence, decreased Leydig cell number, reduced testis/body weights, and elevated sperm malformations. Histological analysis revealed pronounced testicular damage. Western blotting and immunohistochemistry showed unchanged nuclear receptor subfamily 5 (NR5A1) and insulin-like protein 3 (INSL3), but decreased HSD3B1 in <i>NEK2</i><sup>−/−</sup> mice, leading to lower testosterone levels. Mechanistically, NEK2 knockout suppressed wingless/integrated (Wnt)–β-catenin and activated HIPPO, causing mammalian sterile 20-like protein kinase 2 (MST2)–large tumor suppressor homolog 2 (LATS2)-mediated downregulation of yes-associated protein (YAP).</p>\n </section>\n \n <section>\n \n <h3> Conclusions</h3>\n \n <p>These findings highlight NEK2's essential role in regulating testicular descent and spermatogenesis, implicating it as a potential target for cryptorchidism.</p>\n </section>\n </div>","PeriodicalId":9121,"journal":{"name":"Birth Defects Research","volume":"117 5","pages":""},"PeriodicalIF":1.6000,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Birth Defects Research","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/bdr2.2485","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"DEVELOPMENTAL BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Background

Cryptorchidism, characterized by the failure of testicular descent, is a common congenital disorder adversely affecting male reproductive health. Intriguingly, the NIMA-related kinase 2 (NEK2) gene has been implicated in various cellular processes, but its role in cryptorchidism remains underexplored.

Methods

To elucidate NEK2's role, the researchers utilized NEK2 knockout mice, analyzing testes histology with hematoxylin–eosin (HE) staining and assessing sperm morphology by Diff-Quick staining. Immunohistofluorescence evaluated Leydig cell count, while Western blotting and immunohistochemistry analyzed 3β-hydroxysteroid dehydrogenase 1 (HSD3B1), critical for testosterone synthesis. Mouse testosterone levels were quantified by ELISA, and RT-qPCR examined testicular Wnt–β-catenin and HIPPO pathway expression.

Results

NEK2-deficient mice exhibited significantly increased cryptorchidism incidence, decreased Leydig cell number, reduced testis/body weights, and elevated sperm malformations. Histological analysis revealed pronounced testicular damage. Western blotting and immunohistochemistry showed unchanged nuclear receptor subfamily 5 (NR5A1) and insulin-like protein 3 (INSL3), but decreased HSD3B1 in NEK2^−/− mice, leading to lower testosterone levels. Mechanistically, NEK2 knockout suppressed wingless/integrated (Wnt)–β-catenin and activated HIPPO, causing mammalian sterile 20-like protein kinase 2 (MST2)–large tumor suppressor homolog 2 (LATS2)-mediated downregulation of yes-associated protein (YAP).

Conclusions

These findings highlight NEK2's essential role in regulating testicular descent and spermatogenesis, implicating it as a potential target for cryptorchidism.

查看原文本刊更多论文

NEK2有助于预防隐睾的结局

隐睾症是一种常见的先天性疾病，其特征是睾丸下降失败，对男性生殖健康有不利影响。有趣的是，与nima相关的激酶2 （NEK2）基因与多种细胞过程有关，但其在隐睾症中的作用仍未得到充分研究。方法为了阐明NEK2的作用，研究人员利用NEK2敲除小鼠，用苏木精-伊红（HE）染色分析睾丸组织学，用Diff-Quick染色评估精子形态。免疫组织荧光分析间质细胞计数，免疫印迹和免疫组织化学分析3β-羟基类固醇脱氢酶1 (HSD3B1)，这是睾酮合成的关键。ELISA检测小鼠睾酮水平，RT-qPCR检测睾丸Wnt -β-catenin和HIPPO通路表达。结果nek2缺陷小鼠隐睾发生率显著增加，间质细胞数量减少，睾丸/体重减少，精子畸形发生率升高。组织学分析显示明显的睾丸损伤。Western blotting和免疫组化显示NEK2−/−小鼠的核受体亚家族5 （NR5A1）和胰岛素样蛋白3 （INSL3）不变，但HSD3B1降低，导致睾酮水平降低。机制上，NEK2敲除抑制无翼/整合(Wnt) -β-catenin并激活HIPPO，导致哺乳动物不育20样蛋白激酶2 (MST2) -大肿瘤抑制同源物2 （LATS2）介导的yes-associated protein （YAP）下调。这些发现强调了NEK2在调节睾丸下降和精子发生中的重要作用，暗示它是隐睾症的潜在靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Birth Defects Research Medicine-Embryology

CiteScore

3.60

自引率

9.50%

发文量

153

期刊介绍： The journal Birth Defects Research publishes original research and reviews in areas related to the etiology of adverse developmental and reproductive outcome. In particular the journal is devoted to the publication of original scientific research that contributes to the understanding of the biology of embryonic development and the prenatal causative factors and mechanisms leading to adverse pregnancy outcomes, namely structural and functional birth defects, pregnancy loss, postnatal functional defects in the human population, and to the identification of prenatal factors and biological mechanisms that reduce these risks. Adverse reproductive and developmental outcomes may have genetic, environmental, nutritional or epigenetic causes. Accordingly, the journal Birth Defects Research takes an integrated, multidisciplinary approach in its organization and publication strategy. The journal Birth Defects Research contains separate sections for clinical and molecular teratology, developmental and reproductive toxicology, and reviews in developmental biology to acknowledge and accommodate the integrative nature of research in this field. Each section has a dedicated editor who is a leader in his/her field and who has full editorial authority in his/her area.