title: Neural stem and progenitor cell fate transition requires regulation of Musashi1 function.
abstract: BACKGROUND
  There is increasing evidence of a pivotal role for regulated mRNA translation in control of developmental cell fate transitions. Physiological and pathological stem and progenitor cell self-renewal is maintained by the mRNA-binding protein, Musashi1 through repression of translation of key mRNAs encoding cell cycle inhibitory proteins. The mechanism by which Musashi1 function is modified to allow translation of these target mRNAs under conditions that require inhibition of cell cycle progression, is unknown.
  
  
  RESULTS
  In this study, we demonstrate that differentiation of primary embryonic rat neural stem/progenitor cells (NSPCs) or human neuroblastoma SH-SY5Y cells results in the rapid phosphorylation of Musashi1 on the evolutionarily conserved site serine 337 (S337). Phosphorylation of this site has been shown to be required for cell cycle control during the maturation of Xenopus oocytes. S337 phosphorylation in mammalian NSPCs and human SH-SY5Y cells correlates with the de-repression and translation of a Musashi reporter mRNA and with accumulation of protein from the endogenous Musashi target mRNA, p21(WAF1/CIP1). Inhibition of Musashi regulatory phosphorylation, through expression of a phospho-inhibitory mutant Musashi1 S337A or over-expression of the wild-type Musashi, blocked differentiation of both NSPCs and SH-SY5Y cells. Musashi1 was similarly phosphorylated in NSPCs and SH-SY5Y cells under conditions of nutrient deprivation-induced cell cycle arrest. Expression of the Musashi1 S337A mutant protein attenuated nutrient deprivation-induced NSPC and SH-SY5Y cell death.
  
  
  CONCLUSIONS
  Our data suggest that in response to environmental cues that oppose cell cycle progression, regulation of Musashi function is required to promote target mRNA translation and cell fate transition. Forced modulation of Musashi1 function may present a novel therapeutic strategy to oppose pathological stem cell self-renewal.
authors.affiliation: Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, 4301 W. Markham, Slot 814, Little Rock, AR, 72205, USA. Angus@UAMS.edu.|Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, 4301 W. Markham, Little Rock, AR, 72205, USA. Angus@UAMS.edu.
authors.forename: Angus M
authors.initials: AM
authors.lastname: MacNicol
authors.affiliation: Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, 4301 W. Markham, Slot 814, Little Rock, AR, 72205, USA. HardyLindaL@UAMS.edu.
authors.forename: Linda L
authors.initials: LL
authors.lastname: Hardy
authors.affiliation: Department of Biostatistics, University of Arkansas for Medical Sciences, 4301 W. Markham, Little Rock, AR, 72205, USA. SpencerHoraceJ@uams.edu.
authors.forename: Horace J
authors.initials: HJ
authors.lastname: Spencer
authors.affiliation: Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, 4301 W. Markham, Slot 814, Little Rock, AR, 72205, USA. Mel@UAMS.edu.|Center for Translational Neuroscience, University of Arkansas for Medical Sciences, 4301 W. Markham, Little Rock, AR, 72205, USA. Mel@UAMS.edu.
authors.forename: Melanie C
authors.initials: MC
authors.lastname: MacNicol
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D045744:Cell Line, Tumor; D019070:Cell Lineage; D002478:Cells, Cultured; D006801:Humans; D009419:Nerve Tissue Proteins / Q000502:physiology*; D058953:Neural Stem Cells / Q000166:cytology*; D010766:Phosphorylation; D016601:RNA-Binding Proteins / Q000502:physiology*; D051381:Rats
chemical_list: C491297:MSI1 protein, human; C491296:Msi1 protein, rat; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins