title: Wnt signaling regulates neuronal differentiation of cortical intermediate progenitors.
abstract: Cortical intermediate progenitors (IPs) comprise a secondary neuronal progenitor pool that arises from radial glia (RG). IPs are essential for generating the correct number of cortical neurons, but the factors that regulate the expansion and differentiation of IPs in the embryonic cortex are essentially unknown. In this study, we show that the Wnt-β-catenin pathway (canonical Wnt pathway) regulates IP differentiation into neurons. Upregulation of Wnt-β-catenin signaling by overexpression of Wnt3a in the neocortex induced early differentiation of IPs into neurons and the accumulation of these newly born neurons at the subventricular zone/intermediate zone border. Long-term overexpression of Wnt3a led to cortical dysplasia associated with the formation of large neuronal heterotopias. Conversely, downregulation of Wnt-β-catenin signaling with Dkk1 during mid and late stages of neurogenesis inhibited neuronal production. Consistent with previous reports, we show that Wnt-β-catenin signaling also promotes RG self-renewal. Thus, our findings show differential effects of the Wnt-β-catenin pathway on distinct groups of cortical neuronal progenitors: RG self-renewal and IP differentiation. Moreover, our findings suggest that dysregulation of Wnt signaling can lead to developmental defects similar to human cortical malformation disorders.
authors.affiliation: Program in Developmental Biology, University of California, San Francisco, San Francisco, California 94143, USA.
authors.forename: Roeben N
authors.initials: RN
authors.lastname: Munji
authors.forename: Youngshik
authors.initials: Y
authors.lastname: Choe
authors.forename: Guangnan
authors.initials: G
authors.lastname: Li
authors.forename: Julie A
authors.initials: JA
authors.lastname: Siegenthaler
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Pleasure
mesh_terms: D000818:Animals; D002552:Cerebral Ventricles / Q000502:physiology; D015536:Down-Regulation; D018274:Electroporation; D004622:Embryo, Mammalian; D005260:Female; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D019579:Neocortex / Q000378:metabolism / Q000502:physiology*; D058953:Neural Stem Cells / Q000378:metabolism / Q000502:physiology*; D055495:Neurogenesis / Q000502:physiology*; D009457:Neuroglia / Q000502:physiology; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D011247:Pregnancy; D015398:Signal Transduction / Q000502:physiology*; D015854:Up-Regulation; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: C495267:CTNNB1 protein, mouse; C501127:Dkk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; C555510:WNT3A protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; D051176:beta Catenin