title: Ccm3, a gene associated with cerebral cavernous malformations, is required for neuronal migration.
abstract: Loss of function of cerebral cavernous malformation 3 (CCM3) results in an autosomal dominant cerebrovascular disorder. Here, we uncover a developmental role for CCM3 in regulating neuronal migration in the neocortex. Using cell type-specific gene inactivation in mice, we show that CCM3 has both cell autonomous and cell non-autonomous functions in neural progenitors and is specifically required in radial glia and newly born pyramidal neurons migrating through the subventricular zone, but not in those migrating through the cortical plate. Loss of CCM3 function leads to RhoA activation, alterations in the actin and microtubule cytoskeleton affecting neuronal morphology, and abnormalities in laminar positioning of primarily late-born neurons, indicating CCM3 involvement in radial glia-dependent locomotion and possible interaction with the Cdk5/RhoA pathway. Thus, we identify a novel cytoplasmic regulator of neuronal migration and demonstrate that its inactivation in radial glia progenitors and nascent neurons produces severe malformations of cortical development.
authors.affiliation: Departments of Neurosurgery and Neurobiology, Yale Program on Neurogenetics, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Angeliki
authors.initials: A
authors.lastname: Louvi
authors.forename: Sayoko
authors.initials: S
authors.lastname: Nishimura
authors.forename: Murat
authors.initials: M
authors.lastname: Günel
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D005260:Female; D020786:Hemangioma, Cavernous, Central Nervous System / Q000196:embryology / Q000235:genetics* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019579:Neocortex / Q000196:embryology / Q000378:metabolism; D058953:Neural Stem Cells / Q000502:physiology*; D009457:Neuroglia / Q000502:physiology; D011247:Pregnancy; D015398:Signal Transduction; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D020742:rhoA GTP-Binding Protein
chemical_list: D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; C559318:PDCD10 protein, mouse; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein
keywords: CCM3 (PDCD10); Cell autonomous function; Mouse; Nascent neurons; Neocortex; Radial glia