Aberrant motor axon projection, acetylcholine receptor clustering, and neurotransmission in cyclin-dependent kinase 5 null mice.
Cyclin-dependent kinase (Cdk)5 is a key regulator of neural development. We have previously demonstrated that Cdk5/p35 are localized to the postsynaptic muscle and are implicated in the regulation of neuregulin/ErbB signaling in myotube culture. To further elucidate whether Cdk5 activity contributes to neuromuscular junction (NMJ) development in vivo, the NMJ of Cdk5-/- mice was examined. Consistent with our previous demonstration that Cdk5 phosphorylates ErbB2/3 to regulate its tyrosine phosphorylation, we report here that the phosphorylation of ErbB2 and ErbB3 and the ErbB2 kinase activity are reduced in Cdk5-deficient muscle. In addition, Cdk5-/- mice also display morphological abnormalities at the NMJ pre- and postsynaptically. Whereas the outgrowth of the main nerve trunk is grossly normal, the intramuscular nerve projections exhibit profuse and anomalous branching patterns in the Cdk5-/- embryos. The central band of acetylcholine receptor (AChR) clusters is also wider in Cdk5-/- diaphragms, together with the absence of S100 immunoreactivity along the phrenic nerve during late embryonic stages. Moreover, we unexpectedly discovered that the agrin-induced formation of large AChR clusters is significantly increased in primary muscle cultures prepared from Cdk5-null mice and in C2C12 myotubes when Cdk5 activity was suppressed. These abnormalities are accompanied by elevated frequency of miniature endplate potentials in Cdk5-null diaphragm. Taken together, our findings reveal the essential role of Cdk5 in regulating the development of motor axons and neuromuscular synapses in vivo.
Fu
Amy K Y
AK
Department of Biochemistry, Biotechnology Research Institute, and Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China.
Ip
Fanny C F
FC
Fu
Wing-Yu
WY
Cheung
Janet
J
Wang
Jerry H
JH
Yung
Wing-Ho
WH
Ip
Nancy Y
NY
D000818:Animals; D001369:Axons / Q000378:metabolism*; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism*; D003964:Diaphragm / Q000294:innervation / Q000378:metabolism; D004594:Electrophysiology; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000502:physiology; D017403:In Situ Hybridization; D051379:Mice; D018345:Mice, Knockout; D009046:Motor Neurons / Q000166:cytology / Q000378:metabolism; D009469:Neuromuscular Junction / Q000002:abnormalities / Q000033:anatomy & histology / Q000502:physiology; D010791:Phrenic Nerve / Q000166:cytology / Q000378:metabolism; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000378:metabolism; D011950:Receptors, Cholinergic / Q000378:metabolism*; D009418:S100 Proteins / Q000378:metabolism; D012583:Schwann Cells / Q000166:cytology / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology*
D051360:Cyclin-Dependent Kinase 5; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D011950:Receptors, Cholinergic; D009418:S100 Proteins; C495906:Cdk5 protein, mouse