TableEdit

Fu, AK, Ip, FC, Fu, WY, Cheung, J, Wang, JH, Yung, WH and Ip, NY (2005) Aberrant motor axon projection, acetylcholine receptor clustering, and neurotransmission in cyclin-dependent kinase 5 null mice. Proc. Natl. Acad. Sci. U.S.A. 102:15224-9

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.

PubMed PMC1257743 Online version:10.1073/pnas.0507678102

Animals; Axons/metabolism; Cells, Cultured; Cyclin-Dependent Kinase 5/genetics; Cyclin-Dependent Kinase 5/metabolism; Diaphragm/innervation; Diaphragm/metabolism; Electrophysiology; Embryo, Mammalian/anatomy & histology; Embryo, Mammalian/physiology; In Situ Hybridization; Mice; Mice, Knockout; Motor Neurons/cytology; Motor Neurons/metabolism; Neuromuscular Junction/abnormalities; Neuromuscular Junction/anatomy & histology; Neuromuscular Junction/physiology; Phrenic Nerve/cytology; Phrenic Nerve/metabolism; Rats; Receptor, erbB-2/metabolism; Receptor, erbB-3/metabolism; Receptors, Cholinergic/metabolism; S100 Proteins/metabolism; Schwann Cells/cytology; Schwann Cells/metabolism; Synaptic Transmission/physiology