title: Let-7 and miR-125 cooperate to prime progenitors for astrogliogenesis.
abstract: The molecular basis of astrocyte differentiation and maturation is poorly understood. As microRNAs have important roles in cell fate transitions, we set out to study their function during the glial progenitor cell (GPC) to astrocyte transition. Inducible deletion of all canonical microRNAs in GPCs in vitro led to a block in the differentiation to astrocytes. In an unbiased screen, the reintroduction of let-7 and miR-125 families of microRNAs rescued differentiation. Let-7 and miR-125 shared many targets and functioned in parallel to JAK-STAT signaling, a known regulator of astrogliogenesis. While individual knockdown of shared targets did not rescue the differentiation phenotype in microRNA-deficient GPCs, overexpression of these targets in wild-type GPCs blocked differentiation. This finding supports the idea that microRNAs simultaneously suppress multiple mRNAs that inhibit differentiation. MicroRNA-regulated transcripts exhibited concordant changes during in vivo differentiation and were enriched for a gene set upregulated in glioblastomas, consistent with validity of using the in vitro model to study in vivo events. These findings provide insight into the microRNAs and the genes they regulate in this important cell fate transition.
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Center for Reproductive Sciences and Department of Urology, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Archana
authors.initials: A
authors.lastname: Shenoy
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Center for Reproductive Sciences and Department of Urology, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Danial
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Center for Reproductive Sciences and Department of Urology, University of California San Francisco, San Francisco, CA, USA blellochr@stemcell.ucsf.edu.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Blelloch
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000502:physiology*; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology; D002454:Cell Differentiation / Q000502:physiology; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D005910:Glioma / Q000235:genetics / Q000473:pathology; D053612:Janus Kinases / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009457:Neuroglia / Q000166:cytology; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000502:physiology
chemical_list: D020413:3' Untranslated Regions; C474044:Dgcr8 protein, mouse; D035683:MicroRNAs; C527468:Mirn125 microRNA, mouse; D016601:RNA-Binding Proteins; D050791:STAT Transcription Factors; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C542687:mirnlet7 microRNA, mouse; D053612:Janus Kinases
keywords: Let‐7; astrocytes; differentiation; miR‐125; microRNAs