Perinatal abrogation of Cdk5 expression in brain results in neuronal migration defects

doi:10.1073/pnas.0307322101

Perinatal abrogation of Cdk5 expression in brain results in neuronal migration defects

^*Functional Genomics Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892; ^†Laboratory for Developmental Neurobiology, Brain Science Institute, RIKEN, Wako, Saitama 351-0198, Japan; and ^‡Laboratory of Neurochemistry and ^¶Developmental and Metabolic Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892

Contributed by Roscoe O. Brady, December 29, 2003

Abstract

Cyclin-dependent kinase 5 (Cdk5) is essential for the proper development of the CNS, as is evident from the perinatal lethality of conventional Cdk5 knockout (Cdk5-/-) mice. Cdk5 is also implicated in numerous complex functions of the adult CNS such as synaptic transmission, synaptic plasticity, and neuronal signaling. To elucidate the molecular roles of Cdk5 in the adult CNS, we have abrogated neuronal expression of Cdk5 in perinatal mice by using a cre-loxP system. The Cdk5-loxP flanked mice were crossed with the cre-transgenic mice in which the cre expression is driven by the murine neurofilament-heavy chain promoter, resulting in generation of viable Cdk5 conditional knockout mice with the restricted deletion of the Cdk5 gene in specific neurons beginning around embryonic day 16.5. Twenty-five percent of the Cdk5 conditional knockout mice carrying the heterozygous cre allele had neuronal migration defects confined to brain areas where neuronal migration continues through the perinatal period. These results indicate that abrogation of Cdk5 expression in mature neurons results in a viable mouse model that offers further opportunities to investigate the molecular roles of Cdk5 in the adult CNS.

Footnotes

↵ ∥ To whom correspondence should be addressed at: Functional Genomics Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Building 30, Room 527, Bethesda, MD 20892-4395. E-mail: ak40m{at}nih.gov.
↵ § Present address: Center for Dementia Research, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY 10962.
Abbreviations: Cdk, cyclin-dependent kinase; E16.5, embryonic day 16.5; ES, embryonic stem; KO, knockout; NFH, neurofilament-heavy chain; mNFH, murine NFH.