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A Novel Regulatory Axis, CHD1L-MicroRNA 486-Matrix Metalloproteinase 2, Controls Spermatogonial Stem Cell Properties.
- Source :
-
Molecular and cellular biology [Mol Cell Biol] 2019 Feb 04; Vol. 39 (4). Date of Electronic Publication: 2019 Feb 04 (Print Publication: 2019). - Publication Year :
- 2019
-
Abstract
- Spermatogonial stem cells (SSCs) are unipotent germ cells that are at the foundation of spermatogenesis and male fertility. However, the underlying molecular mechanisms governing SSC stemness and growth properties remain elusive. We have recently identified chromodomain helicase/ATPase DNA binding protein 1-like (Chd1l) as a novel regulator for SSC survival and self-renewal, but how these functions are controlled by Chd1l remains to be resolved. Here, we applied high-throughput small RNA sequencing to uncover the microRNA (miRNA) expression profiles controlled by Chd1l and showed that the expression levels of 124 miRNA transcripts were differentially regulated by Chd1l in SSCs. KEGG pathway analysis shows that the miRNAs that are differentially expressed upon Chd1l repression are significantly enriched in the pathways associated with stem cell pluripotency and proliferation. As a proof of concept, we demonstrate that one of the most highly upregulated miRNAs, miR-486, controls SSC stemness gene expression and growth properties. The matrix metalloproteinase 2 (MMP2) gene has been identified as a novel miR-486 target gene in the context of SSC stemness gene regulation and growth properties. Data from cotransfection experiments showed that Chd1l, miR-486, and MMP2 work in concert in regulating SSC stemness gene expression and growth properties. Finally, our data also revealed that MMP2 regulates SSC stemness gene expression and growth properties through activating β-catenin signaling by cleaving N-cadherin and increasing β-catenin nuclear translocation. Our data demonstrate that Chd1l-miR-486-MMP2 is a novel regulatory axis governing SSC stemness gene expression and growth properties, offering a novel therapeutic opportunity for treating male infertility.<br /> (Copyright © 2019 American Society for Microbiology.)
- Subjects :
- Adult Germline Stem Cells cytology
Animals
Cell Proliferation physiology
Cells, Cultured
DNA Helicases genetics
DNA-Binding Proteins genetics
Male
Matrix Metalloproteinase 2 genetics
Mice
MicroRNAs genetics
Pluripotent Stem Cells cytology
Pluripotent Stem Cells metabolism
Spermatogenesis physiology
Spermatogonia metabolism
Testis cytology
Testis metabolism
Transcription Factors metabolism
Adult Germline Stem Cells metabolism
DNA Helicases metabolism
DNA-Binding Proteins metabolism
Matrix Metalloproteinase 2 metabolism
MicroRNAs metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1098-5549
- Volume :
- 39
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Molecular and cellular biology
- Publication Type :
- Academic Journal
- Accession number :
- 30455250
- Full Text :
- https://doi.org/10.1128/MCB.00357-18