Celsr3 is required in motor neurons to steer their axons in the hindlimb
Copyright policy )Celsr3 is required in motor neurons to steer their axons in the hindlimb
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.
Frizzled Receptors -- metabolism, Male, Cells, Knockout, Cell Surface -- genetics -- metabolism, Green Fluorescent Proteins, Tibial Nerve -- cytology -- embryology -- physiology, Receptors, Cell Surface, Hindlimb -- abnormalities -- innervation, Mice, Pregnancy, Ephrin-A2 -- metabolism, Peroneal Nerve -- cytology -- embryology -- physiology, Receptors, Motor Neurons -- physiology -- ultrastructure, Green Fluorescent Proteins -- genetics, Animals, Humans, Signal Transduction -- physiology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Cells, Cultured, Cadherins -- genetics -- metabolism, Mice, Knockout, Motor Neurons, Axons -- physiology, Cultured, Ephrin-A5 -- metabolism, Ephrin-A2, Peroneal Nerve, Sciences bio-médicales et agricoles, Cadherins, Ephrin-A5, Axons, Frizzled Receptors, Hindlimb, Clubfoot, HEK293 Cells, Clubfoot -- embryology -- genetics, Female, Signal Transduction
Frizzled Receptors -- metabolism, Male, Cells, Knockout, Cell Surface -- genetics -- metabolism, Green Fluorescent Proteins, Tibial Nerve -- cytology -- embryology -- physiology, Receptors, Cell Surface, Hindlimb -- abnormalities -- innervation, Mice, Pregnancy, Ephrin-A2 -- metabolism, Peroneal Nerve -- cytology -- embryology -- physiology, Receptors, Motor Neurons -- physiology -- ultrastructure, Green Fluorescent Proteins -- genetics, Animals, Humans, Signal Transduction -- physiology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Cells, Cultured, Cadherins -- genetics -- metabolism, Mice, Knockout, Motor Neurons, Axons -- physiology, Cultured, Ephrin-A5 -- metabolism, Ephrin-A2, Peroneal Nerve, Sciences bio-médicales et agricoles, Cadherins, Ephrin-A5, Axons, Frizzled Receptors, Hindlimb, Clubfoot, HEK293 Cells, Clubfoot -- embryology -- genetics, Female, Signal Transduction
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