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Author Notes:

Correspondence should be addressed to Dr. Yue Feng, Department of Pharmacology, Emory University School of Medicine, 1510 Clifton Road, Atlanta, GA 30322. E-mail:yfeng@emory.edu.

W.L., M.E.A., Y.R., J.Q.Z., and Y.F. designed research; W.L., M.E.A., Y.R., L.K., G.L., and A.N.B. performed research; W.L., M.E.A., Y.R., L.K., and Y.F. analyzed data; W.L., M.E.A., and Y.F. wrote the paper.

We thank Dr. Itzhak Fischer for the anti-MAP1B antibody; Dr. Li-Huei Tsai and Dr. James Bibb for providing the p39−/− mice; and Dr. Asheebo Rojas for advice on KA-induced seizure.

The authors declare no competing financial interests.


Research Funding:

This work was supported by National Institutes of Health R01s NS093016 and NS070526, and Emory University Research Committee Award to Y.F.

M.E.A. was supported by National Institutes of Health Training Grant 5T32GM008367.

W.L. was supported by the FraXa postdoctoral fellowship.


  • Science & Technology
  • Life Sciences & Biomedicine
  • Neurosciences
  • Neurosciences & Neurology
  • axon development
  • Cdk5 activators
  • Cyclin-dependent kinase 5
  • dendritic spine
  • phosphorylation
  • seizure

p39 Is Responsible for Increasing Cdk5 Activity during Postnatal Neuron Differentiation and Governs Neuronal Network Formation and Epileptic Responses


Journal Title:

Journal of Neuroscience Nursing


Volume 36, Number 44


, Pages 11283-11294

Type of Work:

Article | Final Publisher PDF


Two distinct protein cofactors, p35 and p39, independently activate Cyclin-dependent kinase 5 (Cdk5), which plays diverse roles in normal brain function and the pathogenesis of many neurological diseases. The initial discovery that loss of p35 impairs neuronal migration in the embryonic brain prompted intensive research exploring the function of p35-dependent Cdk5 activity. In contrast, p39 expression is restricted to the postnatal brain and its function remains poorly understood. Despite the robustly increased Cdk5 activity during neuronal differentiation, which activator is responsible for enhancing Cdk5 activation and how the two distinct activators direct Cdk5 signaling to govern neuronal network formation and function still remains elusive. Here we report that p39, but not p35, is selectively upregulated by histone acetylation-mediated transcription, which underlies the robust increase of Cdk5 activity during rat and mouse neuronal differentiation. The loss of p39 attenuates overall Cdk5 activity in neurons and preferentially affects phosphorylation of specific Cdk5 targets, leading to aberrant axonal growth and impaired dendritic spine and synapse formation. In adult mouse brains, p39 deficiency results in dysregulation of p35 and Cdk5 targets in synapses. Moreover, in contrast to the proepileptic phenotype caused by the lack of p35, p39 loss leads to deficits in maintaining seizure activity and induction of immediate early genes that control hippocampal excitability. Together, our studies demonstrate essential roles of p39 in neuronal network development and function. Furthermore, our data support a model in which Cdk5 activators play nonoverlapping and even opposing roles to govern balanced Cdk5 signaling in the postnatal brain.

Copyright information:

© 2016 the authors

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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