• PMID: 29022902
• Gene Name: STK11
• Condition: Regulating spermatid differentiation
• Association: Associated
• Sex: Male
• Infertility type: Male infertility

Differential regulation of spermatogenic process by Lkb1 isoforms in mouse testis

Kong F, Wang M, Huang X, Yue Q, Wei X, Dou X, Peng X, Jia Y, Zheng K, Wu T, Yan J, Li J.

Liver serine/threonine kinase B1 (LKB1) is a tumor suppressor associated with the pathogenesis of Peutz-Jeghers syndrome. Affected males are at increased risk of developing Sertoli cell tumors and display defective spermatogenesis. Male mice lacking the short isoform (Lkb1(S)) of Lkb1 were sterile and exhibited abnormal spermiogenesis. In addition to the short isoform, the long isoform of Lkb1 (Lkb1(L)) is also expressed in testis; however, the requirement of the long isoform for fertility and the functional difference between the isoforms remain unknown. Herein, different from the spermiation failure reported in Lkb1(S) knockout mice, conditional deletion (cKO) of both isoforms of Lkb1 in germ cells resulted in male sterility stemming from defects in acrosome formation, as well as nuclear elongation and condensation during spermatid differentiation. Additionally, cKO mice showed a progressive germ cell loss that was never reported in mice with Lkb1(S) deletion. Further experiments revealed that the defect resulted from the failure of spermatogonial stem/progenitor cells (SPCs) maintenance. Although increased mTORC1 activity in postnatal cKO testes was consistent with a tendency toward germline stem cell differentiation, in vivo inhibition of the pathway by rapamycin treatment failed to rescue the phenotype. Concurrently, we detected a significant reduction of mitochondrial activity in Lkb1deficient SPCs. The results suggest that the regulation of LKB1 on SPCs' maintenance is associated with mitochondrial functions but not through the mTOR signaling pathway. In summary, our study supports different roles of Lkb1 isoforms in spermatogenesis with Lkb1(L) directing SPCs maintenance, and Lkb1(L) and Lkb1(S) coordinately regulating spermatid differentiation. FAU - Kong, Feifei AU - Kong F AD - State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China. FAU - Wang, Mei AU - Wang M AD - State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China. FAU - Huang, Xiaojing AU - Huang X AD - State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210008, China. FAU - Yue, Qiuling AU - Yue Q AD - State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China. FAU - Wei, Xiang AU - Wei X AD - State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China. FAU - Dou, Xiaowei AU - Dou X AD - State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China. FAU - Peng, Xiaoxu AU - Peng X AD - State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China. FAU - Jia, Yuanyuan AU - Jia Y AD - State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China. FAU - Zheng, Ke AU - Zheng K AUID- ORCID: 0000-0001-9762-6605 AD - State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China. FAU - Wu, Tinghe AU - Wu T AD - Department of Biotechnology and Biomedicine, Yangtze Delta Region Institutes of Tsinghua University, Jiaxing 314006, China. FAU - Yan, Jun AU - Yan J AD - State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210008, China. AD - Collaborative Innovation Center for Genetics and Development, Shanghai 200438, China.