title: Thalamic WNT3 Secretion Spatiotemporally Regulates the Neocortical Ribosome Signature and mRNA Translation to Specify Neocortical Cell Subtypes.
abstract: Neocortical development requires tightly controlled spatiotemporal gene expression. However, the mechanisms regulating ribosomal complexes and the timed specificity of neocortical mRNA translation are poorly understood. We show that active mRNA translation complexes (polysomes) contain ribosomal protein subsets that undergo dynamic spatiotemporal rearrangements during mouse neocortical development. Ribosomal protein specificity within polysome complexes is regulated by the arrival of in-growing thalamic axons, which secrete the morphogen Wingless-related MMTV (mouse mammary tumor virus) integration site 3 (WNT3). Thalamic WNT3 release during midneurogenesis promotes a change in the levels of Ribosomal protein L7 in polysomes, thereby regulating neocortical translation machinery specificity. Furthermore, we present an RNA sequencing dataset analyzing mRNAs that dynamically associate with polysome complexes as neocortical development progresses, and thus may be regulated spatiotemporally at the level of translation. Thalamic WNT3 regulates neocortical translation of two such mRNAs, Foxp2 and Apc, to promote FOXP2 expression while inhibiting APC expression, thereby driving neocortical neuronal differentiation and suppressing oligodendrocyte maturation, respectively. This mechanism may enable targeted and rapid spatiotemporal control of ribosome composition and selective mRNA translation in complex developing systems like the neocortex.
  
  
  CONCLUSIONS
  The neocortex is a highly complex circuit generating the most evolutionarily advanced complex cognitive and sensorimotor functions. An intricate progression of molecular and cellular steps during neocortical development determines its structure and function. Our goal is to study the steps regulating spatiotemporal specificity of mRNA translation that govern neocortical development. In this work, we show that the timed secretion of Wingless-related MMTV (mouse mammary tumor virus) integration site 3 (WNT3) by ingrowing axons from the thalamus regulates the combinatorial composition of ribosomal proteins in developing neocortex, which we term the "neocortical ribosome signature." Thalamic WNT3 further regulates the specificity of mRNA translation and development of neurons and oligodendrocytes in the neocortex. This study advances our overall understanding of WNT signaling and the spatiotemporal regulation of mRNA translation in highly complex developing systems.
authors.affiliation: Department of Neuroscience & Cell Biology, Robert Wood Johnson Medical School and.
authors.forename: Matthew L
authors.identifier: http://orcid.org/0000-0002-7359-0318
authors.initials: ML
authors.lastname: Kraushar
authors.affiliation: Department of Neuroscience & Cell Biology, Robert Wood Johnson Medical School and.
authors.forename: Barbara
authors.initials: B
authors.lastname: Viljetic
authors.affiliation: Department of Neuroscience & Cell Biology, Robert Wood Johnson Medical School and.
authors.forename: H R Sagara
authors.initials: HR
authors.lastname: Wijeratne
authors.affiliation: Department of Neuroscience & Cell Biology, Robert Wood Johnson Medical School and.
authors.forename: Kevin
authors.initials: K
authors.lastname: Thompson
authors.affiliation: Department of Cell Biology & Neuroscience, Rutgers University, Piscataway, New Jersey 08854, and.
authors.forename: Xinfu
authors.initials: X
authors.lastname: Jiao
authors.affiliation: Department of Neuroscience & Cell Biology, Robert Wood Johnson Medical School and.
authors.forename: Jack W
authors.initials: JW
authors.lastname: Pike
authors.affiliation: Inserm, UMR-S839, Sorbonne Universités, Pierre et Marie Curie Université Paris 06, Institut du Fer à Moulin, Paris 75005, France.
authors.forename: Vera
authors.initials: V
authors.lastname: Medvedeva
authors.affiliation: Inserm, UMR-S839, Sorbonne Universités, Pierre et Marie Curie Université Paris 06, Institut du Fer à Moulin, Paris 75005, France.
authors.forename: Matthias
authors.initials: M
authors.lastname: Groszer
authors.affiliation: Department of Cell Biology & Neuroscience, Rutgers University, Piscataway, New Jersey 08854, and.
authors.forename: Megerditch
authors.initials: M
authors.lastname: Kiledjian
authors.affiliation: Department of Cell Biology & Neuroscience, Rutgers University, Piscataway, New Jersey 08854, and.
authors.forename: Ronald P
authors.initials: RP
authors.lastname: Hart
authors.affiliation: Department of Neuroscience & Cell Biology, Robert Wood Johnson Medical School and roko.rasin@rutgers.edu.
authors.forename: Mladen-Roko
authors.identifier: http://orcid.org/0000-0003-3063-6096
authors.initials: MR
authors.lastname: Rasin
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D019579:Neocortex / Q000166:cytology* / Q000378:metabolism; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012270:Ribosomes / Q000235:genetics / Q000378:metabolism*; D013788:Thalamus / Q000378:metabolism*; D060508:Wnt3 Protein / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D060508:Wnt3 Protein; C555508:Wnt3 protein, mouse
keywords: Wnt; mRNA translation; neocortex; ribosome; thalamocortical