Aberrant motor axon projection, acetylcholine receptor clustering, and neurotransmission in cyclin-dependent kinase 5 null mice
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AbstractCyclin-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.
All Author(s) ListFu AKY, Ip FCF, Fu WY, Cheung J, Wang JH, Yung WH, Ip NY
Journal nameProceedings of the National Academy of Sciences
Volume Number102
Issue Number42
Pages15224 - 15229
LanguagesEnglish-United Kingdom
Keywordsagrin; Cdk5; ErbB receptor; neuromuscular junction
Web of Science Subject CategoriesMultidisciplinary Sciences; MULTIDISCIPLINARY SCIENCES; Science & Technology - Other Topics

Last updated on 2021-24-09 at 00:50