http://onlinelibrary.wiley.com/doi/10.1002/stem.1861/abstract
DOI: 10.1002/stem.1861
ABSTRACT
A comprehensive
understanding of adult neurogenesis is essential for the development of
effective strategies to enhance endogenous neurogenesis in the damaged
brain. Olfactory interneurons arise throughout life from stem cells
residing in the subventricular zone of the lateral ventricle. Neural
precursors then migrate along the rostral migratory stream (RMS) to the
olfactory bulb. To ensure a continuous supply of adult-born
interneurons, precursor proliferation, migration and differentiation
must be tightly coordinated. Here we show that the netrin/RGM receptor,
Neogenin, is a key regulator of adult neurogenesis. Neogenin loss-of-function (Neogt/gt)
mice exhibit a specific reduction in adult-born calretinin interneurons
in the olfactory granule cell layer. In the absence of Neogenin
neuroblasts fail to migrate into the olfactory bulb and instead
accumulate in the RMS. In vitro migration assays confirmed that
Neogenin is required for Netrin-1-mediated neuroblast migration and
chemoattraction. Unexpectedly, we also identified a novel role for
Neogenin as a regulator of the neuroblast cell cycle. We observed that
those neuroblasts able to reach the Neogt/gt
olfactory bulb failed to undergo terminal differentiation. Cell cycle
analysis revealed an increase in the number of S-phase neuroblasts
within the Neogt/gt RMS and a significant reduction
in the number of neuroblasts exiting the cell cycle, providing an
explanation for the loss of mature calretinin interneurons in the
granule cell layer. Therefore, Neogenin acts to synchronize neuroblast
migration and terminal differentiation through the regulation of
neuroblast cell cycle kinetics within the neurogenic microenvironment of
the RMS. Stem Cells 2014
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