Postnatal neuronal proliferation in mice lacking Ink4d and Kip1 inhibitors of cyclin-dependent kinases. Proc Natl Acad Sci U S A 1999 Nov 09;96(23):13462-7
Date
11/11/1999Pubmed ID
10557343Pubmed Central ID
PMC23970DOI
10.1073/pnas.96.23.13462Scopus ID
2-s2.0-0033539696 (requires institutional sign-in at Scopus site) 154 CitationsAbstract
Development of the central nervous system requires proliferation of neuronal and glial cell precursors followed by their subsequent differentiation in a highly coordinated manner. The timing of neuronal cell cycle exit and differentiation is likely to be regulated in part by inhibitors of cyclin-dependent kinases. Overlapping and sustained patterns of expression of two cyclin-dependent kinases, p19(Ink4d) and p27(Kip1), in postmitotic brain cells suggested that these proteins may be important in actively repressing neuronal proliferation. Animals derived from crosses of Ink4d- null with Kip1-null mice exhibited bradykinesia, proprioceptive abnormalities, and seizures, and died at about 18 days after birth. Metabolic labeling of live animals with bromodeoxyuridine at postnatal days 14 and 18, combined with immunolabeling of neuronal markers, showed that subpopulations of central nervous system neurons were proliferating in all parts of the brain, including normally dormant cells of the hippocampus, cortex, hypothalamus, pons, and brainstem. These cells also expressed phosphorylated histone H3, a marker for late G(2) and M-phase progression, indicating that neurons were dividing after they had migrated to their final positions in the brain. Increased proliferation was balanced by cell death, resulting in no gross changes in the cytoarchitecture of the brains of these mice. Therefore, p19(Ink4d) and p27(Kip1) cooperate to maintain differentiated neurons in a quiescent state that is potentially reversible.
Author List
Zindy F, Cunningham JJ, Sherr CJ, Jogal S, Smeyne RJ, Roussel MFMESH terms used to index this publication - Major topics in bold
AnimalsApoptosis
Brain
Carrier Proteins
Cell Cycle Proteins
Cell Differentiation
Cell Division
Cyclin-Dependent Kinase Inhibitor p16
Cyclin-Dependent Kinase Inhibitor p19
Cyclin-Dependent Kinase Inhibitor p27
Cyclin-Dependent Kinases
Female
Male
Mice
Mice, Inbred C57BL
Microtubule-Associated Proteins
Neurons
Tumor Suppressor Proteins
