title: Huntingtin-Mediated Multipolar-Bipolar Transition of Newborn Cortical Neurons Is Critical for Their Postnatal Neuronal Morphology.
abstract: In the developing cortex, projection neurons undergo multipolar-bipolar transition, radial-directed migration, and maturation. The contribution of these developmental steps to the structure of the adult cortex is not completely understood. Here, we report that huntingtin (HTT), the protein mutated in Huntington's disease, is enriched in polarizing projection neurons. The depletion of HTT in postmitotic projection neurons leads to the mislocalization of layer-specific neuronal populations in the mouse neocortex. HTT is required for the multipolar-bipolar transition of projection neurons and for the maintenance of their bipolar shape during their radial migration. HTT mediates these effects in vivo through the regulation of RAB11-dependent N-Cadherin trafficking. Importantly, HD pathological HTT alters RAB11-dependent neuronal migration. Finally, we show that the cortical defects resulting from the postmitotic loss of HTT specifically during embryonic development affect neuronal morphology at adulthood. Our data reveal a new HTT-RAB11-N-Cadherin pathway regulating multipolar-bipolar transition with direct implications for mature brain. VIDEO ABSTRACT.
authors.affiliation: University Grenoble Alpes, Grenoble Institut des Neurosciences, GIN, 38000 Grenoble, France; INSERM, U1216, 38000 Grenoble, France.
authors.forename: Monia
authors.initials: M
authors.lastname: Barnat
authors.affiliation: University Grenoble Alpes, Grenoble Institut des Neurosciences, GIN, 38000 Grenoble, France; INSERM, U1216, 38000 Grenoble, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Le Friec
authors.affiliation: University Grenoble Alpes, Grenoble Institut des Neurosciences, GIN, 38000 Grenoble, France; INSERM, U1216, 38000 Grenoble, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Benstaali
authors.affiliation: University Grenoble Alpes, Grenoble Institut des Neurosciences, GIN, 38000 Grenoble, France; INSERM, U1216, 38000 Grenoble, France. Electronic address: sandrine.humbert@univ-grenoble-alpes.fr.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Humbert
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015820:Cadherins / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics*; D016764:Cell Polarity; D002540:Cerebral Cortex / Q000166:cytology / Q000254:growth & development; D004195:Disease Models, Animal; D000071058:Huntingtin Protein / Q000235:genetics*; D006816:Huntington Disease / Q000235:genetics*; D051379:Mice; D019579:Neocortex / Q000166:cytology / Q000254:growth & development*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010455:Peptides; D021381:Protein Transport; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D000099193:rab11 GTP-Binding Proteins
chemical_list: D015820:Cadherins; D000071058:Huntingtin Protein; D010455:Peptides; D020691:rab GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins; C489083:Cdh2 protein, mouse; C506812:Htt protein, mouse; C097188:polyglutamine
keywords: Huntington disease; N-cadherin; RAB11; cortical development; huntingtin; migration; multipolar-bipolar transition; neuronal morphology; polarization; trafficking