title: FOXO3 promotes quiescence in adult muscle stem cells during the process of self-renewal.
abstract: Skeletal muscle stem cells, or "satellite cells" (SCs), are required for the regeneration of damaged muscle tissue. Although SCs self-renew during regeneration, the mechanisms that govern SC re-entry into quiescence remain elusive. We show that FOXO3, a member of the forkhead family of transcription factors, is expressed in quiescent SCs (QSCs). Conditional deletion of Foxo3 in QSCs impairs self-renewal and increases the propensity of SCs to adopt a differentiated fate. Transcriptional analysis of SCs lacking FOXO3 revealed a downregulation of Notch signaling, a key regulator of SC quiescence. Conversely, overexpression of Notch intracellular domain (NICD) rescued the self-renewal deficit of FOXO3-deficient SCs. We show that FOXO3 regulates NOTCH1 and NOTCH3 receptor expression and that decreasing expression of NOTCH1 and NOTCH3 receptors phenocopies the effect of FOXO3 deficiency in SCs. We demonstrate that FOXO3, perhaps by activating Notch signaling, promotes the quiescent state during SC self-renewal in adult muscle regeneration.
authors.affiliation: Paul F. Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, CA 94305, USA ; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Suchitra D
authors.initials: SD
authors.lastname: Gopinath
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Ashley E
authors.initials: AE
authors.lastname: Webb
authors.affiliation: Paul F. Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, CA 94305, USA ; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Brunet
authors.affiliation: Paul F. Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, CA 94305, USA ; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA ; Neurology Service and Rehabilitation Research and Developmental Center of Excellence, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Rando
mesh_terms: D053687:Adult Stem Cells / Q000166:cytology* / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000502:physiology; D051763:PAX7 Transcription Factor / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D012038:Regeneration / Q000235:genetics; D016192:Resting Phase, Cell Cycle / Q000235:genetics*; D032496:Satellite Cells, Skeletal Muscle / Q000166:cytology* / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D051763:PAX7 Transcription Factor; D012333:RNA, Messenger; D051880:Receptors, Notch
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