Wnt signaling regulates intermediate precursor production in the postnatal dentate gyrus by regulating CXCR4 expression.

Previous studies have examined the role of diverse signaling pathways in dentate neurogenesis, but how these signaling pathways are integrated remains unknown. Using mice that allow genetic manipulation of type 1 radial progenitors in the dentate, we show that forced induction of Wnt signaling leads to expansion of the intermediate progenitor cell (IPC) pool while selective activation of Sonic hedgehog (Shh) signaling drives neurogenesis without significant expansion of IPCs. Thus, both Wnt and Shh signaling are proneurogenic, but they act in distinct manners when their signaling is forced in subgranular zone radial progenitors. We examined potential targets of the Wnt pathway in these cells and found that Cxcr4 is a direct target of Lef1 in dentate gyrus progenitors and that loss of Cxcr4 in postnatal neurogenesis decreases the production of IPCs. This suggests that Wnt activation of dentate gyrus progenitors induces Cxcl12 signaling by regulating receptor expression. This study provides evidence that distinct morphogenic pathways have notably different roles in regulating ongoing dentate neurogenesis.