title: An eIF4E1/4E-T complex determines the genesis of neurons from precursors by translationally repressing a proneurogenic transcription program.
abstract: Here, we have addressed the mechanisms that determine genesis of the correct numbers of neurons during development, focusing on the embryonic cortex. We identify in neural precursors a repressive complex involving eIF4E1 and its binding partner 4E-T that coordinately represses translation of proteins that determine neurogenesis. This eIF4E1/4E-T complex is present in granules with the processing body proteins Lsm1 and Rck, and disruption of this complex causes premature and enhanced neurogenesis and neural precursor depletion. Analysis of the 4E-T complex shows that it is highly enriched in mRNAs encoding transcription factors and differentiation-related proteins. These include the proneurogenic bHLH mRNAs, which colocalize with 4E-T in granules and whose protein products are aberrantly upregulated following knockdown of eIF4E, 4E-T, or processing body proteins. Thus, neural precursors are transcriptionally primed to generate neurons, but an eIF4E/4E-T complex sequesters and represses translation of proneurogenic proteins to determine appropriate neurogenesis.
authors.affiliation: Program in Neuroscience and Mental Health, Hospital for Sick Children, Toronto, ON M5G 1L7, Canada.
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.affiliation: Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Craig A
authors.initials: CA
authors.lastname: Smibert
authors.affiliation: Program in Neuroscience and Mental Health, Hospital for Sick Children, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: dkaplan@sickkids.ca.
authors.forename: David R
authors.initials: DR
authors.lastname: Kaplan
authors.affiliation: Program in Neuroscience and Mental Health, Hospital for Sick Children, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: fredam@sickkids.ca.
authors.forename: Freda D
authors.initials: FD
authors.lastname: Miller
mesh_terms: D000818:Animals; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D055495:Neurogenesis / Q000235:genetics*; D009474:Neurons / Q000502:physiology*; D029543:Nucleocytoplasmic Transport Proteins / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: C411571:EIF4ENIF1 protein, human; D039561:Eukaryotic Initiation Factor-4E; D029543:Nucleocytoplasmic Transport Proteins