Molecular regulation of postnatal neurogenesis in the mammalian subventricular zone-olfactory bulb pathway.

摘要

Neural precursors persist throughout life in the rodent forebrain subventricular zone (SVZ). These precursors generate neuroblasts that migrate to the olfactory bulb to form interneurons. Cells isolated from the SVZ behave like neural stem cells capable of differentiating into neurons, astrocytes and oligodendrocytes in vitro. Despite significant attention, the precise mechanisms regulating postnatal neurogenesis in the mammalian brain remain unclear.; Because the components for retinoid signaling are present in the SVZ-olfactory bulb pathway, we examined the influence of retinoic acid (RA) on postnatal neurogenesis. Using SVZ neurosphere cultures and parasagittal brain slices derived from postnatal mouse, we found that RA increased neurogenesis by enhancing the proliferation of SVZ neuroblasts. Electroporation of dominant-negative retinoid receptors into the SVZ blocked neuroblast migration to the olfactory bulb and altered progenitor morphology. Moreover, the administration of a RA synthesis inhibitor to neonatal mice decreased in vivo SVZ neuroblast proliferation. These results indicate that RA is a potent mitogen for SVZ neuroblasts and is required for their migration to the olfactory bulb.; Hepatocyte growth factor (HGF) influences cell motility, proliferation and morphogenesis. In neonatal mouse brain, HGF and its receptor are present in the SVZ-olfactory bulb pathway. Using in vitro assays and HGF deficient mice, we found that HGF promotes cell proliferation and maintains SVZ cells in a progenitor state. HGF also acts as chemoattractant for SVZ neuroblasts in co-culture assays. Decreased HGF signaling induces ectopic SVZ neuroblast migration and accelerated migration to the olfactory bulb. These results suggest that HGF is a mitogen for SVZ progenitors, and regulates their differentiation and olfactory bulb migration.; The regulation of persistent neural stem-like cells is poorly understood, in part due to a lack of prospective neural progenitor markers. Sox B1 transcription factors (Sox1-3) are expressed by most progenitors in the embryonic nervous system and influence neural development. We explored Sox3 expression patterns in postnatal mouse brain, and in cultured mouse and human neural progenitors. Sox3 is expressed transiently by proliferating and differentiating neural progenitors in the postnatal mouse SVZ-olfactory bulb pathway and dentate gyrus. In vitro, high Sox3 expression levels in undifferentiated, mouse SVZ or human embryonic stem cell-derived neurospheres decline markedly with differentiation. Therefore, Sox3 labels neural progenitors during specific developmental stages, and likely plays a role in neural stem cell maintenance. A better understanding of neural progenitor cell regulation in the neonatal and adult mammalian brain should provide insight into developmental mechanisms and lead to strategies for brain repair.