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P27(KIP1) regulates 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.

SUBMITTER: Li X

PROVIDER: S-EPMC3488282 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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p27(KIP1) regulates neurogenesis in the rostral migratory stream and olfactory bulb of the postnatal mouse.

Li Xuekun X Tang Xiaobing X Jablonska Beata B Aguirre Adan A Gallo Vittorio V Luskin Marla B MB

The Journal of neuroscience : the official journal of the Society for Neuroscience 20090301 9

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 gene ...[more]

PMID: 19261886

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Project description:It is poorly understood how progressive brain swelling in experimental cerebral malaria (ECM) evolves in space and over time, and whether mechanisms of inflammation or microvascular sequestration/obstruction dominate the underlying pathophysiology. We therefore monitored in the Plasmodium berghei ANKA-C57BL/6 murine ECM model, disease manifestation and progression clinically, assessed by the Rapid-Murine-Coma-and-Behavioral-Scale (RMCBS), and by high-resolution in vivo MRI, including sensitive assessment of early blood-brain-barrier-disruption (BBBD), brain edema and microvascular pathology. For histological correlation HE and immunohistochemical staining for microglia and neuroblasts were obtained. Our results demonstrate that BBBD and edema initiated in the olfactory bulb (OB) and spread along the rostral-migratory-stream (RMS) to the subventricular zone of the lateral ventricles, the dorsal-migratory-stream (DMS), and finally to the external capsule (EC) and brainstem (BS). Before clinical symptoms (mean RMCBS = 18.5±1) became evident, a slight, non-significant increase of quantitative T2 and ADC values was observed in OB+RMS. With clinical manifestation (mean RMCBS = 14.2±0.4), T2 and ADC values significantly increased along the OB+RMS (p = 0.049/p = 0.01). Severe ECM (mean RMCBS = 5±2.9) was defined by further spread into more posterior and deeper brain structures until reaching the BS (significant T2 elevation in DMS+EC+BS (p = 0.034)). Quantitative automated histological analyses confirmed microglial activation in areas of BBBD and edema. Activated microglia were closely associated with the RMS and neuroblasts within the RMS were severely misaligned with respect to their physiological linear migration pattern. Microvascular pathology and ischemic brain injury occurred only secondarily, after vasogenic edema formation and were both associated less with clinical severity and the temporal course of ECM. Altogether, we identified a distinct spatiotemporal pattern of microglial activation in ECM involving primarily the OB+RMS axis, a distinct pathway utilized by neuroblasts and immune cells. Our data suggest significant crosstalk between these two cell populations to be operative in deeper brain infiltration and further imply that the manifestation and progression of cerebral malaria may depend on brain areas otherwise serving neurogenesis.

Dataset Information

P27(KIP1) regulates neurogenesis in the rostral migratory stream and olfactory bulb of the postnatal mouse.

Publications

p27(KIP1) regulates neurogenesis in the rostral migratory stream and olfactory bulb of the postnatal mouse.

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