Myotubularin related protein 7 is essential for the spermatogonial stem cell homeostasis via PI3K/AKT signaling

Dan Zhao; Cong Shen; Tingting Gao; Hong Li; Yueshuai Guo; Feng Li; Chenchen Liu; Yuanyuan Liu; Xia Chen; Xi Zhang; Yangyang Wu; Yi Yu; Meng Lin; Yan Yuan; Xiaofang Chen; Xiaoyan Huang; Shenmin Yang; Jun Yu; Jun Zhang; Bo Zheng

doi:10.1080/15384101.2019.1661174

Myotubularin related protein 7 is essential for the spermatogonial stem cell homeostasis via PI3K/AKT signaling

Cell Cycle. 2019 Oct;18(20):2800-2813. doi: 10.1080/15384101.2019.1661174. Epub 2019 Sep 3.

Authors

Dan Zhao¹, Cong Shen^{2

3}, Tingting Gao⁴, Hong Li², Yueshuai Guo^{3

5}, Feng Li^{1

6}, Chenchen Liu³, Yuanyuan Liu^{2

3}, Xia Chen⁷, Xi Zhang³, Yangyang Wu³, Yi Yu², Meng Lin³, Yan Yuan⁸, Xiaofang Chen¹, Xiaoyan Huang³, Shenmin Yang², Jun Yu⁷, Jun Zhang³, Bo Zheng^{2

3}

Affiliations

¹ Fourth Affiliated Hospital of Jiangsu University , Zhenjiang , China.
² Center for Reproduction and Genetics, Suzhou Municipal Hospital, the Affiliated Suzhou Hospital of Nanjing Medical University , Suzhou , China.
³ State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University , Nanjing , China.
⁴ Center of Clinical Reproductive Medicine, the Affiliated Changzhou Matemity and Child Health Care Hospital of Nanjing Medical University , Changzhou , China.
⁵ The Affiliated Wuxi Matemity and Child Health Care Hospital of Nanjing Medical University , Wuxi , China.
⁶ Reproductive Medicine Center, Northern Jiangsu Province Hospital , Yangzhou , China.
⁷ Department of Obstetrics and Gynecology, Affiliated Hospital of Jiangsu University, Jiangsu University , Zhenjiang , China.
⁸ Human Reproductive and Genetic center, Affiliated Hospital of Jiangnan University , Wuxi , China.

Abstract

Myotubularin related protein 7 (MTMR7), a key member of the MTMR family, depicts phosphatase activity and is involved in myogenesis and tumor growth. We have previously identified MTMR7 in the proteomic profile of mouse spermatogonial stem cell (SSC) maturation and differentiation, implying that MTMR7 is associated with neonatal testicular development. In this study, to further explore the distribution and function of MTMR7 in mouse testis, we studied the effect of Mtmr7 knockdown on neonatal testicular development by testicular and SSC culture methods. Our results revealed that MTMR7 is exclusively located in early germ cells. Deficiency of MTMR7 by morpholino in neonatal testis caused excessive SSC proliferation, which was attributable to the aberrant PI3K/AKT signaling activation. Altogether, our study demonstrates that MTMR7 maintains SSC homeostasis by inhibiting PI3K/AKT signaling activation.

Keywords: Myotubularin related protein 7 (MTMR7); PI3K/AKT signaling; germ cells; spermatogonial stem cell (SSC).

MeSH terms

Animals
Apoptosis / genetics
Cell Cycle / genetics
Cell Proliferation / genetics
Cells, Cultured
Chromones / pharmacology
Gene Knockdown Techniques
Homeostasis
Male
Mice
Mice, Inbred ICR
Morpholines / pharmacology
Morpholinos / pharmacology
Organoids
Phosphatidylinositol 3-Kinases / metabolism*
Phosphoinositide-3 Kinase Inhibitors / pharmacology
Protein Tyrosine Phosphatases, Non-Receptor / genetics
Protein Tyrosine Phosphatases, Non-Receptor / metabolism*
Proto-Oncogene Proteins c-akt / metabolism*
Seminiferous Tubules / cytology
Seminiferous Tubules / metabolism
Signal Transduction / genetics
Spermatogenesis / genetics*
Spermatogonia / cytology
Spermatogonia / metabolism*
Stem Cells / metabolism
Testis / metabolism*

Substances

Chromones
Morpholines
Morpholinos
Phosphoinositide-3 Kinase Inhibitors
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Proto-Oncogene Proteins c-akt
Mtmr7 protein, mouse
Protein Tyrosine Phosphatases, Non-Receptor

Grants and funding

This work was supported by the Suzhou Key Medical Center(SZZX201505), Jiangsu Provincial Medical Innovation Team(CXTDB2017013), Suzhou Introduced Project of Clinical Medical Expert Team (SZYJTD201708), Suzhou Key Laboratory of male reproduction research (SZS201718), Suzhou Science and Technology Development Project (SYS201566), Clinical Medical Foundation of Chinese Medical Association (18010330762), Open Fund of State Key Laboratory of Reproductive Medicine of Nanjing Medical University (SKLRM-KA201704), Basic Program of Nanjing Medical University (2017NJMU163), Natural Science Foundation of Jiangsu Province (BK20160177 and BK20170562), the Science and Technology Project of Changzhou (CJ20180040), Matemity and Child Health Foundation of Jiangsu Province (F201865), National Natural Science Foundation of China (31701298, 81601338), Natural Science Foundation of the Jiangsu Higher Education Institutions of China (16KJB310006) and Key Research Foundation of Zhenjiang Social Development (SH2016028, SH2017013 and SH2018065)..