title: Fat1 interacts with Fat4 to regulate neural tube closure, neural progenitor proliferation and apical constriction during mouse brain development.
abstract: Mammalian brain development requires coordination between neural precursor proliferation, differentiation and cellular organization to create the intricate neuronal networks of the adult brain. Here, we examined the role of the atypical cadherins Fat1 and Fat4 in this process. We show that mutation of Fat1 in mouse embryos causes defects in cranial neural tube closure, accompanied by an increase in the proliferation of cortical precursors and altered apical junctions, with perturbations in apical constriction and actin accumulation. Similarly, knockdown of Fat1 in cortical precursors by in utero electroporation leads to overproliferation of radial glial precursors. Fat1 interacts genetically with the related cadherin Fat4 to regulate these processes. Proteomic analysis reveals that Fat1 and Fat4 bind different sets of actin-regulating and junctional proteins. In vitro data suggest that Fat1 and Fat4 form cis-heterodimers, providing a mechanism for bringing together their diverse interactors. We propose a model in which Fat1 and Fat4 binding coordinates distinct pathways at apical junctions to regulate neural progenitor proliferation, neural tube closure and apical constriction.
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, M5G 1X5, Canada.
authors.forename: Caroline
authors.initials: C
authors.lastname: Badouel
authors.affiliation: Neuroscience and Mental Health Program, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Zander
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, M5G 1X5, Canada.
authors.forename: Nicole
authors.initials: N
authors.lastname: Liscio
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, M5G 1X5, Canada.
authors.forename: Mazdak
authors.initials: M
authors.lastname: Bagherie-Lachidan
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Richelle
authors.initials: R
authors.lastname: Sopko
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, M5G 2M9, Canada.
authors.forename: Etienne
authors.initials: E
authors.lastname: Coyaud
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, M5G 2M9, Canada.
authors.forename: Brian
authors.initials: B
authors.lastname: Raught
authors.affiliation: Neuroscience and Mental Health Program, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada Department of Molecular Genetics, University of Toronto, Toronto, Ontario, M5S 1A8, Canada.
authors.forename: Freda D
authors.initials: FD
authors.lastname: Miller
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, M5G 1X5, Canada Department of Molecular Genetics, University of Toronto, Toronto, Ontario, M5S 1A8, Canada mcneill@lunenfeld.ca.
authors.forename: Helen
authors.initials: H
authors.lastname: McNeill
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000196:embryology*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000502:physiology*; D055785:Gene Knockdown Techniques; D051379:Mice; D008856:Microscopy, Fluorescence; D058953:Neural Stem Cells / Q000502:physiology*; D054259:Neural Tube / Q000196:embryology* / Q000378:metabolism; D001616:beta-Galactosidase
chemical_list: D015820:Cadherins; C506555:Fat4 protein, mouse; C502406:fat1 protein, mouse; D001616:beta-Galactosidase
keywords: Apical constriction; Brain; Fat cadherins; Mammalian cortex development; Neural tube defects; Radial glial precursor