title: Cdk12 and Cdk13 regulate axonal elongation through a common signaling pathway that modulates Cdk5 expression.
abstract: Cdk12 and Cdk13 are Cdc2-related proteins that share 92% identity in their kinase domains. Using in situ hybridization and Western blot analysis, we detected the expression of Cdk12 and Cdk13 mRNAs and their proteins in developing mouse embryos, especially during development of the nervous system. We explored the roles of Cdk12 and Cdk13 in neuronal differentiation using the P19 neuronal differentiation model. Upon knockdown of Cdk12 or Cdk13, no effect on differentiated cell numbers was detected, but a substantial decrease of numbers of neurons with long neurites was identified. Similarly, knockdown of Cdk12 or Cdk13 in primarily cultured cortical neurons shortens the averaged axonal length. A microarray analysis was used to examine changes in gene expression after knockdown or overexpression of Cdk12 and we identified Cdk5 as a molecule potentially involved in mediating the effect of Cdk12 and Cdk13. Depletion of Cdk12 or Cdk13 in P19 cells significantly reduces Cdk5 expression at both the mRNA and protein levels. Expression of Cdk5 protein in the developing mouse brain is also reduced in conditional Cdk12-knockout mice in proportion to the residual amount of Cdk12 protein present. This suggests that the reduced axonal outgrowth after knockdown of Cdk12 or Cdk13 might be due to lower Cdk5 expression. Furthermore, overexpression of Cdk5 protein in P19 cells was able to partially rescue the neurite outgrowth defect observed when Cdk12 or Cdk13 is depleted. Together, these findings suggest that Cdk12 and Cdk13 regulate axonal elongation through a common signaling pathway that modulates Cdk5 expression.
authors.affiliation: Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 11221, Taiwan, ROC.
authors.forename: Hong-Ru
authors.initials: HR
authors.lastname: Chen
authors.affiliation: Institute of Neuroscience, National Yang-Ming University, Taipei 11221, Taiwan, ROC.
authors.forename: Guan-Ting
authors.initials: GT
authors.lastname: Lin
authors.affiliation: Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 11221, Taiwan, ROC.
authors.forename: Chun-Kai
authors.initials: CK
authors.lastname: Huang
authors.affiliation: Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 11221, Taiwan, ROC; Brain Research Center, National Yang-Ming University, Taipei 11221, Taiwan, ROC. Electronic address: mjfann@ym.edu.tw.
authors.forename: Ming-Ji
authors.initials: MJ
authors.lastname: Fann
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology*; D016203:CDC2 Protein Kinase; D002277:Carcinoma / Q000473:pathology; D002452:Cell Count; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D002540:Cerebral Cortex; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics / Q000378:metabolism*; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D014404:Tubulin / Q000378:metabolism
chemical_list: D014404:Tubulin; C462941:beta3 tubulin, mouse; C000593691:CDK13 protein, mouse; D051360:Cyclin-Dependent Kinase 5; D016203:CDC2 Protein Kinase; C000593690:CDK12 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases
keywords: Axonal elongation; Cyclin-dependent kinase; Gene expression