TY - JOUR
T1 - Regulation of neuronal migration by Dchs1-Fat4 planar cell polarity
AU - Zakaria, Sana
AU - Mao, Yaopan
AU - Kuta, Anna
AU - Ferreira De Sousa, Catia
AU - Gaufo, Gary O.
AU - McNeill, Helen
AU - Hindges, Robert
AU - Guthrie, Sarah
AU - Irvine, Kenneth D.
AU - Francis-West, Philippa H.
N1 - Funding Information:
All mouse procedures were approved by the Rutgers University Institutional Animal Care and Use Committee or by King’s College London in accordance with established guidelines for animal care. This research was funded by the BBSRC (BB/G021074/1 and BB/K001671/1, P.H.F.-W.), King’s College London Scholarship (S.Z.), and the Howard Hughes Medical Institute (K.D.I.). We thank Magdalena Götz, Tanoue Ishiuchi, Kieran Jones, Clemens Kieckers, Ivo Lieberam, Liqun Luo, Anne Moon, Michelle Studer, Alfredo Varela-Echavarria, and departmental colleagues for helpful discussions and gifts of plasmids and reagents, and we thank Giovanna Lalli, Jeremy Green, Eileen Gentleman, and Michele Studer for comments on the manuscript.
PY - 2014/7/21
Y1 - 2014/7/21
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84905052687&partnerID=8YFLogxK
U2 - 10.1016/j.cub.2014.05.067
DO - 10.1016/j.cub.2014.05.067
M3 - Article
C2 - 24998526
AN - SCOPUS:84905052687
SN - 0960-9822
VL - 24
SP - 1620
EP - 1627
JO - Current Biology
JF - Current Biology
IS - 14
ER -