Mice lacking p35, a neuronal specific activator of Cdk5, display cortical lamination defects, seizures, and adult lethality.
The adult mammalian cortex is characterized by a distinct laminar structure generated through a well-defined pattern of neuronal migration. Successively generated neurons are layered in an "inside-out" manner to produce six cortical laminae. We demonstrate here that p35, the neuronal-specific activator of cyclin-dependent kinase 5, plays a key role in proper neuronal migration. Mice lacking p35, and thus p35/cdk5 kinase activity, display severe cortical lamination defects and suffer from sporadic adult lethality and seizures. Histological examination reveals that the mutant mice lack the characteristic laminated structure of the cortex. Neuronal birth-dating experiments indicate a reversed packing order of cortical neurons such that earlier born neurons reside in superficial layers and later generated neurons occupy deep layers. The phenotype of p35 mutant mice thus demonstrates that the formation of cortical laminar structure depends on the action of the p35/cdk5 kinase.
Chae
T
T
Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Kwon
Y T
YT
Bronson
R
R
Dikkes
P
P
Li
E
E
Tsai
L H
LH
D000818:Animals; D002540:Cerebral Cortex / Q000196:embryology / Q000473:pathology* / Q000503:physiopathology*; D003433:Crosses, Genetic; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases; D005314:Embryonic and Fetal Development; D017353:Gene Deletion; D015698:Genomic Library; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants; D009474:Neurons / Q000502:physiology*; D016366:Open Reading Frames; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D011995:Recombination, Genetic; D012640:Seizures / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology
D051360:Cyclin-Dependent Kinase 5; D017346:Protein Serine-Threonine Kinases; C495905:CDK5 protein, human; C495906:Cdk5 protein, mouse; D018844:Cyclin-Dependent Kinases