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.

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

Grant support

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)..