The extracellular region of Lrp4 is sufficient to mediate neuromuscular synapse formation.
Neuromuscular synapse formation requires an exchange of signals between motor neurons and muscle. Agrin, supplied by motor neurons, binds to Lrp4 in muscle, stimulating phosphorylation of MuSK and recruitment of a signaling complex essential for synapse-specific transcription and anchoring of key proteins in the postsynaptic membrane. Lrp4, like the LDLR and other Lrp-family members, contains an intracellular region with motifs that can regulate receptor trafficking, as well as assembly of an intracellular signaling complex. Here, we show that the intracellular region of Lrp4 is dispensable for Agrin to stimulate MuSK phosphorylation and clustering of acetylcholine receptors in cultured myotubes. Moreover, muscle-selective expression of a Lrp4-CD4 chimera, composed of the extracellular and transmembrane regions of Lrp4 and the intracellular region of CD4, rescues neuromuscular synapse formation and the neonatal lethality of lrp4 mutant mice, demonstrating that Lrp4, lacking the Lrp4 intracellular region, is sufficient for presynaptic and postsynaptic differentiation.
Molecular Neurobiology Program, Helen L. and Martin S. Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine, NYU Medical School, 540 First Avenue, New York, NY 10016, USA.
Andrea M
AM
Gomez
Steven J
SJ
Burden
D018171:Agrin / Q000235:genetics / Q000378:metabolism; D000818:Animals; D026502:LDL-Receptor Related Proteins; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009469:Neuromuscular Junction / Q000166:cytology / Q000196:embryology*; D010766:Phosphorylation / Q000502:physiology; D017434:Protein Structure, Tertiary; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011950:Receptors, Cholinergic / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*
D018171:Agrin; D026502:LDL-Receptor Related Proteins; C116415:Lrp4 protein, mouse; D009124:Muscle Proteins; D011950:Receptors, Cholinergic; D011973:Receptors, LDL; C511695:MuSK protein, mouse; D020794:Receptor Protein-Tyrosine Kinases