title: Celsr3 is required in motor neurons to steer their axons in the hindlimb.
abstract: The cadherin Celsr3 regulates the directional growth and targeting of axons in the CNS, but whether it acts in collaboration with or in parallel to other guidance cues is unknown. Furthermore, the function of Celsr3 in the peripheral nervous system is still largely unexplored. Here we show that Celsr3 mediates pathfinding of motor axons innervating the hindlimb. In mice, Celsr3-deficient axons of the peroneal nerve segregate from those of the tibial nerve but fail to extend dorsally, and they stall near the branch point. Mutant axons respond to repulsive ephrinA-EphA forward signaling and glial cell-derived neurotrophic factor (GDNF). However, they are insensitive to attractive EphA-ephrinA reverse signaling. In transfected cells, Celsr3 immunoprecipitates with ephrinA2, ephrinA5, Ret, GDNF family receptor α1 (GFRα1) and Frizzled3 (Fzd3). The function of Celsr3 is Fzd3 dependent but Vangl2 independent. Our results provide evidence that the Celsr3-Fzd3 pathway interacts with EphA-ephrinA reverse signaling to guide motor axons in the hindlimb.
authors.affiliation: Developmental Neurobiology, Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Chai
authors.affiliation: Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China.
authors.forename: Libing
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Unité d'Etude du Mouvement (UEM), Neurologie, Erasme, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Mario
authors.initials: M
authors.lastname: Manto
authors.affiliation: Centre National de la Recherche Scientifique, Institut de Biologie du Développement de Marseille Luminy, Aix-Marseille Université, Marseille, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Helmbacher
authors.affiliation: Laboratory of Neural Differentiation, Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Clotman
authors.affiliation: 1] Developmental Neurobiology, Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium. [2] Developmental Neurobiology, WELBIO, Brussels, Belgium.
authors.forename: André M
authors.initials: AM
authors.lastname: Goffinet
authors.affiliation: Developmental Neurobiology, Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Fadel
authors.initials: F
authors.lastname: Tissir
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology*; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D003025:Clubfoot / Q000196:embryology / Q000235:genetics; D036383:Ephrin-A2 / Q000378:metabolism; D036386:Ephrin-A5 / Q000378:metabolism; D005260:Female; D051157:Frizzled Receptors / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D057809:HEK293 Cells; D006614:Hindlimb / Q000002:abnormalities / Q000294:innervation*; D006801:Humans; D008297:Male; D018345:Mice, Knockout; D009046:Motor Neurons / Q000502:physiology* / Q000648:ultrastructure; D010543:Peroneal Nerve / Q000166:cytology / Q000196:embryology / Q000502:physiology*; D011247:Pregnancy; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013979:Tibial Nerve / Q000166:cytology / Q000196:embryology / Q000502:physiology*
chemical_list: D015820:Cadherins; C444454:Celsr3 protein, mouse; D036383:Ephrin-A2; D036386:Ephrin-A5; D051157:Frizzled Receptors; C486339:Fzd3 protein, mouse; D011956:Receptors, Cell Surface; D049452:Green Fluorescent Proteins
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