title: Phosphorylation of eIF2α Is a Translational Control Mechanism Regulating Muscle Stem Cell Quiescence and Self-Renewal.
abstract: Regeneration of adult tissues depends on somatic stem cells that remain quiescent yet are primed to enter a differentiation program. The molecular pathways that prevent activation of these cells are not well understood. Using mouse skeletal muscle stem cells as a model, we show that a general repression of translation, mediated by the phosphorylation of translation initiation factor eIF2α at serine 51 (P-eIF2α), is required to maintain the quiescent state. Skeletal muscle stem cells unable to phosphorylate eIF2α exit quiescence, activate the myogenic program, and differentiate, but do not self-renew. P-eIF2α ensures in part the robust translational silencing of accumulating mRNAs that is needed to prevent the activation of muscle stem cells. Additionally, P-eIF2α-dependent translation of mRNAs regulated by upstream open reading frames (uORFs) contributes to the molecular signature of stemness. Pharmacological inhibition of eIF2α dephosphorylation enhances skeletal muscle stem cell self-renewal and regenerative capacity.
authors.affiliation: Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC H3T 1E2, Canada; Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada.
authors.forename: Victoria
authors.initials: V
authors.lastname: Zismanov
authors.affiliation: Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC H3T 1E2, Canada; Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada.
authors.forename: Victor
authors.initials: V
authors.lastname: Chichkov
authors.affiliation: Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC H3T 1E2, Canada; Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; Department of Health Sciences, University of Milan Bicocca, Monza 20900, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Colangelo
authors.affiliation: Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC H3T 1E2, Canada.
authors.forename: Solène
authors.initials: S
authors.lastname: Jamet
authors.affiliation: Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC H3T 1E2, Canada.
authors.forename: Shuo
authors.initials: S
authors.lastname: Wang
authors.affiliation: Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC H3T 1E2, Canada; Department of Oncology, McGill University, Montreal, QC H2W 1S6, Canada.
authors.forename: Alasdair
authors.initials: A
authors.lastname: Syme
authors.affiliation: Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC H3T 1E2, Canada; Department of Oncology, McGill University, Montreal, QC H2W 1S6, Canada.
authors.forename: Antonis E
authors.initials: AE
authors.lastname: Koromilas
authors.affiliation: Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC H3T 1E2, Canada; Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada. Electronic address: colin.crist@mcgill.ca.
authors.forename: Colin
authors.initials: C
authors.lastname: Crist
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D005260:Female; D006720:Homozygote; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology* / Q000378:metabolism*; D032446:Myoblasts / Q000378:metabolism; D016366:Open Reading Frames; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D012038:Regeneration; D032496:Satellite Cells, Skeletal Muscle / Q000166:cytology*; D013234:Stem Cells / Q000166:cytology*
chemical_list: D015852:Eukaryotic Initiation Factor-2; D012333:RNA, Messenger