P27KIP1Regulates Neurogenesis in the Rostral Migratory Stream and Olfactory Bulb of the Postnatal Mouse

Abstract

Neuronal progenitor cells of the anterior subventricular zone (SVZa) migrate along the rostral migratory stream (RMS) to the olfactory bulb, where they exit the cell cycle and differentiate. The molecular mechanisms that regulate SVZa progenitor proliferation and cell-cycle exit are largely undefined. We investigated the role of p27(KIP1) in regulating cell proliferation and survival in the RMS and olfactory bulb between postnatal day 1 (P1) and P14, the peak period of olfactory bulb neuron generation. A large proportion of cells in the RMS and the olfactory bulb express cytoplasmic p27(KIP1), but a small percentage display high nuclear p27(KIP1) immunostaining, which exhibit a caudal(low)-rostral(high) gradient: lowest in the SVZa and highest in the glomerular layer of the olfactory bulb. p27(KIP1) is also present in the nucleus and/or the cytoplasm of neuron-specific type III beta-tubulin(+) cells. Cells with strong nuclear p27(KIP1) expression are BrdU(-) and Ki67(-). The percentage of BrdU(+) cells in the SVZa, RMS, and olfactory bulb is higher in p27(KIP1) null than wild-type (WT) mice at all ages analyzed. Consistent with these findings, p27(KIP1) overexpression in cultured p27(KIP1) null and WT SVZ cells reduced cell proliferation and self-renewal. Finally, in p27(KIP1) null mice, the diameter of the horizontal limb of the RMS is larger than in WT mice, and development of the olfactory bulb granule cell layer is delayed, together with increased apoptotic cell density. Our results indicate that in the postnatal brain, p27(KIP1) regulates the proliferation and survival of neuronal cells in the RMS and olfactory bulb.