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Curr Biol. 2014 Jul 21;24(14):1620-7. doi: 10.1016/j.cub.2014.05.067. Epub 2014 Jul 3.

Regulation of neuronal migration by Dchs1-Fat4 planar cell polarity.

Author information

1
Department of Craniofacial Development and Stem Cell Biology, Dental Institute, King's College London, Guy's Tower, Floor 27, London Bridge, London SE1 9RT, UK.
2
Howard Hughes Medical Institute, Waksman Institute, and Department of Molecular Biology and Biochemistry, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
3
Department of Biology, The University of Texas at San Antonio, One UTSA Circle, San Antonio, TX 78249, USA.
4
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada.
5
MRC Centre for Developmental Neurobiology, 4th Floor New Hunt's House, King's College, Guy's Campus, London SE1 1UL, UK.
6
Howard Hughes Medical Institute, Waksman Institute, and Department of Molecular Biology and Biochemistry, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA. Electronic address: irvine@waksman.rutgers.edu.
7
Department of Craniofacial Development and Stem Cell Biology, Dental Institute, King's College London, Guy's Tower, Floor 27, London Bridge, London SE1 9RT, UK. Electronic address: philippa.francis-west@kcl.ac.uk.

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.

PMID:
24998526
PMCID:
PMC4193925
DOI:
10.1016/j.cub.2014.05.067
[Indexed for MEDLINE]
Free PMC Article
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