Postnatal neuronal proliferation in mice lacking Ink4d and Kip1 inhibitorsof cyclin-dependent kinases

Development of the central nervous system requires proliferation of neurona l and glial cell precursors followed by their subsequent differentiation in a highly coordinated manner. The timing of neuronal cell cycle exit and di fferentiation is likely to be regulated in part by inhibitors of cyclin-dep endent kinases. Overlapping and sustained patterns of expression of two cyc lin-dependent kinases, p(19Ink4d) and p27(Kip1), postmitotic brain cells su ggested that these proteins may be important in actively repressing neurona l proliferation. Animals derived from crosses of Ink4d- null with Kip1-null mice exhibited bradykinesia, proprioceptive abnormalities, and seizures, a nd died at about 18 days after birth. Metabolic labeling of live animals wi th bromodeoxyuridine at postnatal days 14 and 18, combined with immunolabel ing of neuronal markers, showed that subpopulations of central nervous syst em neurons were proliferating in all parts of the brain, including normally dormant cells of the hippocampus. cortex, hypothalamus, pens, and brainste m. These cells also expressed phosphorylated histone H3, a marker for late G(2) and M-phase progression, indicating that neurons were dividing after t hey had migrated to their final positions in the brain. Increased prolifera tion was balanced by cell death, resulting in no gross changes in the cytoa rchitecture of the brains of these mice. Therefore, p(19Ink4d) and p27(Kip1 ) cooperate to maintain differentiated neurons in a quiescent state that is potentially reversible.