Synapse disassembly and formation of new synapses in postnatal muscle upon conditional inactivation of MuSK.
The muscle-specific-kinase MuSK is required for the formation of acetylcholine receptor clusters during embryonic development, but its physiological role in adult muscle is not known. We used the loxP/Cre system in mice to conditionally inactivate MuSK whereby expression of Cre recombinase increases during postnatal development. The MuSK-inactivated mice develop myasthenic symptoms and die prematurely due to severe muscle weakness. The postnatal inactivation of MuSK causes loss of acetylcholine receptors and disassembly of the postsynaptic organization and innervating axons retract but start to grow and branch extensively. Due to the mosaic expression of Cre recombinase, MuSK is not globally inactivated and new synapses are formed aberrantly patterned across the diaphragm. Our findings demonstrate that MuSK kinase activity is required throughout postnatal development to hold up MuSK and AChR levels at endplates. Thus, MuSK and AChR together maintain the functional and structural integrity of the postsynaptic architecture and prevent axon growth.
Hesser
Boris A
BA
Max-Planck-Institut für medizinische Forschung, Jahnstrasse 29, 69120 Heidelberg, Germany.
Henschel
Oliver
O
Witzemann
Veit
V
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D020868:Gene Silencing / Q000502:physiology; D005822:Genetic Vectors / Q000235:genetics; D020439:Growth Cones / Q000378:metabolism; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000166:cytology / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000254:growth & development* / Q000294:innervation* / Q000378:metabolism; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism; D009469:Neuromuscular Junction / Q000254:growth & development* / Q000378:metabolism; D009473:Neuronal Plasticity / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D011950:Receptors, Cholinergic / Q000235:genetics* / Q000378:metabolism; D013570:Synaptic Membranes / Q000235:genetics / Q000378:metabolism; D009435:Synaptic Transmission / Q000235:genetics
D009414:Nerve Growth Factors; D011950:Receptors, Cholinergic; C095714:MUSK protein, human; D020794:Receptor Protein-Tyrosine Kinases; C045073:Cre recombinase; D019426:Integrases; D000109:Acetylcholine