Aberrant motor axon projection, acetylcholine receptor clustering, and neurotransmission in cyclin-dependent kinase 5 null mice

Abstract

Cyclin-dependent kinase (Cdk)5 is a key regulator of neural development. We have previously demonstrated that Cdk5͞p35 are localized to the postsynaptic muscle and are implicated in the regulation of neuregulin͞ErbB 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 ErbB2͞3 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.agrin ͉ Cdk5 ͉ ErbB receptor ͉ neuromuscular junction

Wnt signaling promotes AChR aggregation at the neuromuscular synapse in collaboration with agrin

“…Here we show that diaphragms from Dvl1-null mutants exhibit a more dispersed distribution of AChR clusters. A stronger but similar phenotype has been observed in mutants that affect NMJ development including the agrin, HB9, ChAT, and cdk5 mutants (13,(39)(40)(41). Like agrin mutants, Dvl1 mutants exhibit a more detectable phenotype at E18 than at earlier stages (41).…”

The ERBB3 receptor in cancer and cancer gene therapy

“…26 The mysterious nuclear and nucleolar activities of ERBB3 76,78,79 must be unraveled. Further study is needed of the involvement of non-NRG, non-ERBB regulators of ERBB3, such as CDK5, [122][123][124] BRK, 125 SRC, 126 and MET. 120 The fascinating and widely expressed ERBB3 effector EBP1 has thus far been examined mainly in mammary and prostate cells; [154][155][156][157][158][159][160][161][162][163][164] may it be important also in other cancers where ERBB3 is clearly a player, such as lung and melanoma?…”

“…These results for muscle were confirmed in Cdk5 −/− knockout mice. 124 In a further study, Cdk5 immunoprecipitated from brain extracts was demonstrated to phosphorylate Thr 871 and Ser 1120 in rat Erbb3 in vitro ;125 the consensus sequence of RSRSRSPRPR surrounding Ser 1120 is novel. Physical association of Cdk5 and Erbb3 was confirmed in rat cortical neurons.…”

Cyclin-dependent kinase 5 modulates nociceptive signaling through direct phosphorylation of transient receptor potential vanilloid 1

“…Analysis of the in vivo role of Cdk5 in pain signaling has been restricted due to the embryonic lethality of the Cdk5-knockout mice; however, it should be noted that Cdk5-knockout pups are unresponsive to noxious cutaneous pinch (34). We recently reported an altered basal thermal response in p35-knockout (possess reduced Cdk5 activity) and transgenic p35 overexpressing (possess increased Cdk5 activity) mice (15).…”