Aberrant development of motor axons and neuromuscular synapses in MyoD-null mice.
Myogenic regulatory factors (MRFs), muscle-specific transcription factors, are implicated in the activity-dependent regulation of nicotinic acetylcholine receptor (AChR) subunit genes. Here we show, with immunohistochemistry, Western blotting, and electron microscopy that MyoD, a member of the MRF family, also plays a role in fetal synapse formation. In the diaphragm of 14.5 d gestation (E14.5) wild-type and MyoD-/- mice, AChR clusters (the formation of which is under a muscle intrinsic program) are confined to a centrally located endplate zone. This distribution persists in wild-type adult muscles. However, beginning at E15.5 and extending to the adult, innervated AChR clusters are distributed all over the diaphragm of MyoD-/- mice, extending as far as the insertion of the diaphragm into the ribs. In wild-type muscle, motor axons terminate on clusters adjacent to the main intramuscular nerve; in MyoD-/- muscle, axonal bundles form extensive secondary branches that terminate on the widely distributed clusters. The number of AChR clusters on adult MyoD-/- and wild-type diaphram muscles is similar. Junctional fold density is reduced at MyoD-/- endplates, and the transition from the fetal (alpha, beta, gamma, delta) to adult-type (alpha, beta, delta, epsilon) AChRs is markedly delayed. However, MyoD-/- mice assemble a complex postsynaptic apparatus that includes muscle-specific kinase (MuSK), rapsyn, erbB, and utrophin.
Wang
Zuo-Zhong
ZZ
Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
Washabaugh
Charles H
CH
Yao
Yun
Y
Wang
Jun-Mei
JM
Zhang
Lili
L
Ontell
Martin P
MP
Watkins
Simon C
SC
Rudnicki
Michael A
MA
Ontell
Marcia
M
D000367:Age Factors; D018171:Agrin / Q000494:pharmacology; D000818:Animals; D001369:Axons / Q000473:pathology* / Q000648:ultrastructure; D002478:Cells, Cultured; D003964:Diaphragm / Q000196:embryology / Q000294:innervation / Q000378:metabolism / Q000473:pathology; D007366:Intercostal Muscles / Q000294:innervation / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009046:Motor Neurons / Q000473:pathology*; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D017570:MyoD Protein / Q000235:genetics*; D032446:Myoblasts / Q000166:cytology; D009421:Nervous System Malformations / Q000235:genetics* / Q000473:pathology; D009469:Neuromuscular Junction / Q000473:pathology* / Q000648:ultrastructure; D021122:Protein Subunits / Q000378:metabolism; D011940:Receptor Aggregation; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D011950:Receptors, Cholinergic / Q000378:metabolism
D018171:Agrin; D009124:Muscle Proteins; D017570:MyoD Protein; D021122:Protein Subunits; D011950:Receptors, Cholinergic; C051609:peripheral membrane protein 43K; C095714:MUSK protein, human; D020794:Receptor Protein-Tyrosine Kinases