title: A Smaug2-Based Translational Repression Complex Determines the Balance between Precursor Maintenance versus Differentiation during Mammalian Neurogenesis.
abstract: Here, we have asked about post-transcriptional mechanisms regulating murine developmental neurogenesis, focusing upon the RNA-binding proteins Smaug2 and Nanos1. We identify, in embryonic neural precursors of the murine cortex, a Smaug2 protein/nanos1 mRNA complex that is present in cytoplasmic granules with the translational repression proteins Dcp1 and 4E-T. We show that Smaug2 inhibits and Nanos1 promotes neurogenesis, with Smaug2 knockdown enhancing neurogenesis and depleting precursors, and Nanos1 knockdown inhibiting neurogenesis and maintaining precursors. Moreover, we show that Smaug2 likely regulates neurogenesis by silencing nanos1 mRNA. Specifically, Smaug2 knockdown inappropriately increases Nanos1 protein, and the Smaug2 knockdown-mediated neurogenesis is rescued by preventing this increase. Thus, Smaug2 and Nanos1 function as a bimodal translational repression switch to control neurogenesis, with Smaug2 acting in transcriptionally primed precursors to silence mRNAs important for neurogenesis, including nanos1 mRNA, and Nanos1 acting during the transition to neurons to repress the precursor state.
  
  
  CONCLUSIONS
  The mechanisms instructing neural stem cells to generate the appropriate progeny are still poorly understood. Here, we show that the RNA-binding proteins Smaug2 and Nanos1 are critical regulators of this balance and provide evidence supporting the idea that neural precursors are transcriptionally primed to generate neurons but translational regulation maintains these precursors in a stem cell state until the appropriate developmental time.
authors.affiliation: Programs in Neurosciences and Mental Health and Departments of Molecular Genetics.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Amadei
authors.affiliation: Programs in Neurosciences and Mental Health and.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Zander
authors.affiliation: Programs in Neurosciences and Mental Health and.
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.affiliation: Biochemistry, and.
authors.forename: Jason G
authors.initials: JG
authors.lastname: Dumelie
authors.affiliation: Programs in Neurosciences and Mental Health and.
authors.forename: John P
authors.initials: JP
authors.lastname: Vessey
authors.affiliation: Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada, and Departments of Molecular Genetics.
authors.forename: Howard D
authors.identifier: http://orcid.org/0000-0002-7372-4419
authors.initials: HD
authors.lastname: Lipshitz
authors.affiliation: Departments of Molecular Genetics, Biochemistry, and.
authors.forename: Craig A
authors.initials: CA
authors.lastname: Smibert
authors.affiliation: Programs in Neurosciences and Mental Health and Departments of Molecular Genetics.
authors.forename: David R
authors.initials: DR
authors.lastname: Kaplan
authors.affiliation: Programs in Neurosciences and Mental Health and Departments of Molecular Genetics, Physiology, University of Toronto, Toronto, Ontario M5G 1X5, Canada fredam@sickkids.ca.
authors.forename: Freda D
authors.initials: FD
authors.lastname: Miller
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology / Q000502:physiology*; D005260:Female; D008297:Male; D008322:Mammals; D051379:Mice; D058953:Neural Stem Cells / Q000502:physiology*; D055495:Neurogenesis / Q000502:physiology*; D014176:Protein Biosynthesis / Q000502:physiology; D016601:RNA-Binding Proteins / Q000502:physiology*; D012097:Repressor Proteins / Q000502:physiology*
chemical_list: D016601:RNA-Binding Proteins; D012097:Repressor Proteins; C551897:SAMD4B protein, human; C484506:nanos1 protein, mouse
keywords: Smaug2; nanos1; neurogenesis; radial precursor development; stem cells; translational repression