title: Regulation of neuronal migration by Dchs1-Fat4 planar cell polarity.
abstract: Planar cell polarity (PCP) describes the polarization of cell structures and behaviors within the plane of a tissue. PCP is essential for the generation of tissue architecture during embryogenesis and for postnatal growth and tissue repair, yet how it is oriented to coordinate cell polarity remains poorly understood [1]. In Drosophila, PCP is mediated via the Frizzled-Flamingo (Fz-PCP) and Dachsous-Fat (Fat-PCP) pathways [1-3]. Fz-PCP is conserved in vertebrates, but an understanding in vertebrates of whether and how Fat-PCP polarizes cells, and its relationship to Fz-PCP signaling, is lacking. Mutations in human FAT4 and DCHS1, key components of Fat-PCP signaling, cause Van Maldergem syndrome, characterized by severe neuronal abnormalities indicative of altered neuronal migration [4]. Here, we investigate the role and mechanisms of Fat-PCP during neuronal migration using the murine facial branchiomotor (FBM) neurons as a model. We find that Fat4 and Dchs1 are expressed in complementary gradients and are required for the collective tangential migration of FBM neurons and for their PCP. Fat4 and Dchs1 are required intrinsically within the FBM neurons and extrinsically within the neuroepithelium. Remarkably, Fat-PCP and Fz-PCP regulate FBM neuron migration along orthogonal axes. Disruption of the Dchs1 gradients by mosaic inactivation of Dchs1 alters FBM neuron polarity and migration. This study implies that PCP in vertebrates can be regulated via gradients of Fat4 and Dchs1 expression, which establish intracellular polarity across FBM cells during their migration. Our results also identify Fat-PCP as a novel neuronal guidance system and reveal that Fat-PCP and Fz-PCP can act along orthogonal axes.
authors.affiliation: Department of Craniofacial Development and Stem Cell Biology, King's College London, Dental Institute, Guy's Tower, Floor 27, London Bridge, London, SE1 9RT, UK.
authors.forename: Sana
authors.initials: S
authors.lastname: Zakaria
authors.affiliation: Howard Hughes Medical Institute, Waksman Institute and Department of Molecular Biology and Biochemistry, Rutgers The State University of New Jersey, Piscataway NJ 08854, USA.
authors.forename: Yaopan
authors.initials: Y
authors.lastname: Mao
authors.affiliation: Department of Craniofacial Development and Stem Cell Biology, King's College London, Dental Institute, Guy's Tower, Floor 27, London Bridge, London, SE1 9RT, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Kuta
authors.affiliation: Department of Craniofacial Development and Stem Cell Biology, King's College London, Dental Institute, Guy's Tower, Floor 27, London Bridge, London, SE1 9RT, UK.
authors.forename: Catia Ferreira
authors.initials: CF
authors.lastname: de Sousa
authors.affiliation: Department of Biology, The University of Texas at San Antonio, One UTSA circle, San Antonio, Texas, 78249 USA.
authors.forename: Gary O
authors.initials: GO
authors.lastname: Gaufo
authors.affiliation: The Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, M5G 1X5, Canada.
authors.forename: Helen
authors.initials: H
authors.lastname: McNeill
authors.affiliation: MRC Centre for Developmental Neurobiology, 4th Floor New Hunt's House, King's College, Guy's Campus, London SE1 1UL, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Hindges
authors.affiliation: MRC Centre for Developmental Neurobiology, 4th Floor New Hunt's House, King's College, Guy's Campus, London SE1 1UL, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Guthrie
authors.affiliation: Howard Hughes Medical Institute, Waksman Institute and Department of Molecular Biology and Biochemistry, Rutgers The State University of New Jersey, Piscataway NJ 08854, USA.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Irvine
authors.affiliation: Department of Craniofacial Development and Stem Cell Biology, King's College London, Dental Institute, Guy's Tower, Floor 27, London Bridge, London, SE1 9RT, UK.
authors.forename: Philippa H
authors.initials: PH
authors.lastname: Francis-West
mesh_terms: D000818:Animals; D015820:Cadherins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement; D016764:Cell Polarity / Q000502:physiology*; D004330:Drosophila; D029721:Drosophila Proteins / Q000096:biosynthesis; D018507:Gene Expression Regulation, Developmental; D006056:Golgi Apparatus / Q000502:physiology; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D009046:Motor Neurons / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D015820:Cadherins; C506554:Dchs1 protein, mouse; D029721:Drosophila Proteins; C506555:Fat4 protein, mouse; D008562:Membrane Glycoproteins; C094449:ds protein, Drosophila; C095900:fj protein, Drosophila