title: ColQ controls postsynaptic differentiation at the neuromuscular junction.
abstract: CollagenQ (ColQ) plays an important structural role at vertebrate neuromuscular junctions (NMJs) by anchoring and accumulating acetylcholinesterase (AChE) in the extracellular matrix (ECM). Moreover, ColQ interacts with perlecan/dystroglycan and the muscle-specific receptor tyrosine kinase (MuSK), key molecules in the NMJ formation. MuSK promotes acetylcholine receptor (AChR) clustering in a process mediated by rapsyn, a cytoplasmic protein that stimulates AChR packing in clusters and regulates synaptic gene transcription. Here, we investigated a regulatory role for ColQ by comparing the clustering and expression of synaptic proteins in wild type and ColQ-deficient muscle cells in culture and at NMJ. We show first that AChR clusters are smaller and more densely packed in the absence of ColQ both in vitro and in vivo. Second, we find that like AChRs and rapsyn, MuSK mRNA levels are increased in cultured cells but not in muscles lacking ColQ. However, membrane-bound MuSK is decreased both in vitro and in vivo suggesting that ColQ controls MuSK sorting or stabilization in the muscle membrane. In line with this, our data show that activation of the MuSK signaling pathway is altered in the absence of ColQ leading to (1) perturbation of AChR clustering and/or beta-AChR subunit phosphorylation and (2) modifications of AChR mRNA level due to the lack of ColQ-MuSK interaction. Together, our results demonstrate that ColQ, in addition to its structural role, has important regulatory functions at the synapse by controlling AChR clustering and synaptic gene expression through its interaction with MuSK.
authors.affiliation: Laboratoire de biologie des jonctions neuromusculaires normales et pathologiques, Université Paris Descartes, Inserm U686, 75270 Paris, France.
authors.forename: Séverine M
authors.initials: SM
authors.lastname: Sigoillot
authors.forename: Francine
authors.initials: F
authors.lastname: Bourgeois
authors.forename: Monique
authors.initials: M
authors.lastname: Lambergeon
authors.forename: Laure
authors.initials: L
authors.lastname: Strochlic
authors.forename: Claire
authors.initials: C
authors.lastname: Legay
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D019556:COS Cells; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003094:Collagen / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009469:Neuromuscular Junction / Q000166:cytology / Q000502:physiology*; D017729:Presynaptic Terminals / Q000502:physiology*; D051381:Rats; D011940:Receptor Aggregation / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism / Q000502:physiology; D011950:Receptors, Cholinergic / Q000378:metabolism / Q000502:physiology; D013569:Synapses / Q000502:physiology
chemical_list: D011950:Receptors, Cholinergic; D003094:Collagen; C475048:MuSK protein, rat; D020794:Receptor Protein-Tyrosine Kinases; D000110:Acetylcholinesterase; C533412:ColQ protein, rat