Canonical microRNAs enable differentiation, protect against DNA damage, and promote cholesterol biosynthesis in neural stem cells Journal Article
| Authors: | Liu, Z.; Zhang, C.; Khodadadi-Jamayran, A.; Dang, L.; Han, X.; Kim, K.; Li, H.; Zhao, R. |
| Article Title: | Canonical microRNAs enable differentiation, protect against DNA damage, and promote cholesterol biosynthesis in neural stem cells |
| Abstract: | Neural stem cells (NSCs) have the capacity to differentiate into neurons, astrocytes, and oligodendrocytes, and therefore represent a promising donor tissue source for treating neurodegenerative diseases and repairing injuries of the nervous system. However, it remains unclear how canonical microRNAs (miRNAs), the subset of miRNAs requiring the Drosha-Dgcr8 microprocessor and the type III RNase Dicer for biogenesis, regulate NSCs. In this study, we established and characterized Dgcr8-/- NSCs from conditionally Dgcr8-disrupted mouse embryonic brain. RNA-seq analysis demonstrated that disruption of Dgcr8 in NSCs causes a complete loss of canonical miRNAs and an accumulation of pri-miRNAs. Dgcr8-/- NSCs can be stably propagated in vitro, but progress through the cell cycle at reduced rates. When induced for differentiation, Dgcr8-/- NSCs failed to differentiate into neurons, astrocytes, or oligodendrocytes under permissive conditions. Compared to Dgcr8+/- NSCs, Dgcr8-/- NSCs exhibit significantly increased DNA damage. Comparative RNA-seq analysis and gene set enrichment analysis (GSEA) revealed that Dgcr8-/- NSCs significantly downregulate genes associated with neuronal differentiation, cell cycle progression, DNA replication, protein translation, and DNA damage repair. Furthermore, we discovered that Dgcr8-/- NSCs significantly downregulate genes responsible for cholesterol biosynthesis and demonstrated that Dgcr8-/- NSCs contain lower levels of cholesterol. Together, our data demonstrate that canonical miRNAs play essential roles in enabling lineage specification, protecting DNA against damage, and promoting cholesterol biosynthesis in NSCs. © 2017, Mary Ann Liebert, Inc. |
| Keywords: | cholesterol; neural stem cells; mirna; dgcr8 |
| Journal Title: | Stem Cells and Development |
| Volume: | 26 |
| Issue: | 3 |
| ISSN: | 1547-3287 |
| Publisher: | Mary Ann Liebert, Inc |
| Date Published: | 2017-02-01 |
| Start Page: | 177 |
| End Page: | 188 |
| Language: | English |
| DOI: | 10.1089/scd.2016.0259 |
| PROVIDER: | scopus |
| PUBMED: | 27762676 |
| PMCID: | PMC5312609 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 March 2017 -- Source: Scopus |
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