title: Cdk12 Regulates Neurogenesis and Late-Arising Neuronal Migration in the Developing Cerebral Cortex.
abstract: DNA damage response (DDR) pathways are critical for ensuring that replication stress and various types of DNA lesion do not perturb production of neural cells during development. Cdk12 maintains genomic stability by regulating expression of DDR genes. Mutant mice in which Cdk12 is conditionally deleted in neural progenitor cells (NPCs) die after birth and exhibit microcephaly with a thinner cortical plate and an aberrant corpus callosum. We show that NPCs of mutant mice accumulate at G2 and M phase, and have lower expression of DDR genes, more DNA double-strand breaks and increased apoptosis. In addition to there being fewer neurons, there is misalignment of layers IV-II neurons and the presence of abnormal axonal tracts of these neurons, suggesting that Cdk12 is also required for the migration of late-arising cortical neurons. Using in utero electroporation, we demonstrate that the migrating mutant cells remain within the intermediate zone and fail to adopt a bipolar morphology. Overexpression of Cdk5 brings about a partially restoration of the neurons reaching layers IV-II in the mutant mice. Thus, Cdk12 is crucial to the repair of DNA damage during the proliferation of NPCs and is also central to the proper migration of late-arising neurons.
authors.affiliation: Department of Life Sciences and Institute of Genome Sciences.|Brain Research Center.
authors.forename: Hong-Ru
authors.initials: HR
authors.lastname: Chen
authors.affiliation: Department of Life Sciences and Institute of Genome Sciences.
authors.forename: Hsien-Chia
authors.initials: HC
authors.lastname: Juan
authors.affiliation: Brain Research Center.
authors.forename: Yu-Hui
authors.initials: YH
authors.lastname: Wong
authors.affiliation: Brain Research Center.|Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan 11221, Republic of China.
authors.forename: Jin-Wu
authors.initials: JW
authors.lastname: Tsai
authors.affiliation: Department of Life Sciences and Institute of Genome Sciences.|Brain Research Center.
authors.forename: Ming-Ji
authors.initials: MJ
authors.lastname: Fann
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation / Q000502:physiology; D002540:Cerebral Cortex / Q000254:growth & development* / Q000378:metabolism* / Q000473:pathology; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000502:physiology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008831:Microcephaly / Q000378:metabolism / Q000473:pathology; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009929:Organ Size; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors
chemical_list: D012333:RNA, Messenger; D051360:Cyclin-Dependent Kinase 5; C000593690:CDK12 protein, mouse; C495906:Cdk5 protein, mouse; D018844:Cyclin-Dependent Kinases
keywords: Cdk12; Cdk5; DNA damage response; late-arising neuron; neuronal migration