Abstract
Hippocampal neurogenesis in the dentate gyrus (DG) is controlled by diffusible molecules that modulate neurogenic processes, including cell proliferation, differentiation and survival. To elucidate the mechanisms underlying hippocampal neurogenesis, we investigated the function of draxin, originally identified as a neural chemorepellent, in the regulation of neuronal survival in the DG. Draxin was expressed in Tbr2 (+) late progenitors and NeuroD1 (+) neuroblasts in the dentate granule cell lineage, whereas expression of its receptor DCC (deleted in colorectal cancer) was mainly detectable in neuroblasts. Our phenotypic analysis revealed that draxin deficiency led to enhanced apoptosis of DCC-expressing neuroblasts in the neurogenic areas. Furthermore, in vitro assays using a hippocampal neural stem/progenitor cell (HNSPC) line indicated that draxin inhibited apoptosis in differentiating HNSPCs, which express DCC. Taken together, we postulate that draxin plays a pivotal role in postnatal DG neurogenesis as a dependence receptor ligand for DCC to maintain and promote survival of neuroblasts.
Highlights
In the hippocampal dentate gyrus (DG), granule cell production begins in the embryo and continues throughout life[1,2,3,4]
Given our observation that draxin expression was restricted to the subgranular zone (SGZ; the innermost part of the granule cell layer) of the DG in juveniles (Fig. 1A,A’,B), we sought to determine the type of cells expressing draxin in the SGZ
In accordance with this observation, our findings showed that a mutation in the caspases cleavage site in DCC resulted in decreased apoptosis in differentiating hippocampal neural stem/progenitor cell (HNSPC) in vitro, suggesting that DCC-induced apoptosis in the absence of ligands is mediated through a caspase-dependent mechanism
Summary
In the hippocampal dentate gyrus (DG), granule cell production begins in the embryo and continues throughout life[1,2,3,4]. Compared with DCC, neogenin was expressed more widely in the granule cell lineage including early/late progenitors, neuroblasts and immature neurons (Supplementary Figure S2).
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