Initiation of synapse formation by Wnt-induced MuSK endocytosis.
In zebrafish, the MuSK receptor initiates neuromuscular synapse formation by restricting presynaptic growth cones and postsynaptic acetylcholine receptors (AChRs) to the center of skeletal muscle cells. Increasing evidence suggests a role for Wnts in this process, yet how muscle cells respond to Wnt signals is unclear. Here, we show that in vivo, wnt11r and wnt4a initiate MuSK translocation from muscle membranes to recycling endosomes and that this transition is crucial for AChR accumulation at future synaptic sites. Moreover, we demonstrate that components of the planar cell polarity pathway colocalize to recycling endosomes and that this localization is MuSK dependent. Knockdown of several core components disrupts MuSK translocation to endosomes, AChR localization and axonal guidance. We propose that Wnt-induced trafficking of the MuSK receptor to endosomes initiates a signaling cascade to align pre- with postsynaptic elements. Collectively, these findings suggest a general mechanism by which Wnt signals shape synaptic connectivity through localized receptor endocytosis.
Department of Cell and Developmental Biology, University of Pennsylvania. Philadelphia, PA 19104-6058, USA.
Laura R
LR
Gordon
Katherine D
KD
Gribble
Camille M
CM
Syrett
Michael
M
Granato
D000818:Animals; D030801:Animals, Genetically Modified; D002462:Cell Membrane / Q000378:metabolism; D016764:Cell Polarity; D004705:Endocytosis / Q000502:physiology*; D011992:Endosomes / Q000378:metabolism; D018398:Homeodomain Proteins; D018482:Muscle, Skeletal / Q000166:cytology / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011950:Receptors, Cholinergic / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013569:Synapses / Q000502:physiology* / Q000648:ultrastructure; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000502:physiology*; D060528:Wnt4 Protein / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000099193:rab11 GTP-Binding Proteins
D018398:Homeodomain Proteins; D020794:Receptor Protein-Tyrosine Kinases; D011950:Receptors, Cholinergic; D011993:Recombinant Fusion Proteins; D051153:Wnt Proteins; D060528:Wnt4 Protein; D029961:Zebrafish Proteins; D020691:rab GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins; C490829:MuSK protein, zebrafish; C092568:Wnt11 protein, zebrafish