Wnt Signaling Regulates Intermediate Precursor Production in the Postnatal Dentate Gyrus by Regulating Cxcr4 Expression

Abstract

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.

Hypothalamic radial glia function as self-renewing neural progenitors in the absence of Wnt/ß-catenin signaling

“…Previous work from our laboratory showed that Wnt/β-catenin signaling is required for postembryonic hypothalamic neurogenesis , and other studies have also led to the hypothesis that pathway activity promotes radial glial differentiation (Lee et al, 2006;Wang et al, 2011Wang et al, , 2012Choe and Pleasure, 2012;Varela-Nallar and Inestrosa, 2013). By contrast, Wnt/β-catenin signaling has also been shown to promote the self-renewal and expansion of neural stem cells in the mammalian telencephalic subventricular zone and dentate gyrus (Qu et al, 2010).…”

Chemokines in the balance: maintenance of homeostasis and protection at CNS barriers

“…These factors are critical for the maintenance of adult neurogenesis as Shh promotes proliferation of NPCs (Machold et al, 2003) and manipulation of the Wnt pathway nearly abolishes neurogenesis in the adult hippocampus (Lie et al, 2005). It is now known that CXCR4 is a downstream target of Wnt signaling, suggesting that Wnt induces CXCL12-mediated processes in NPCs via receptor regulation (Choe and Pleasure, 2012). …”

How to make a hippocampal dentate gyrus granule neuron

“…In addition, the interactions between the various signaling pathways active within the neurogenic niche must be closely examined. It has been shown that both SHH and WNT3A regulate the NSC population in the perinatal and adult DG through Sox2-dependent autocrine mechanisms (Favaro et al, 2009) and that each may mediate the proliferation and differentiation in different populations of neural progenitors in the DG during early postnatal and adult neurogenesis (Choe and Pleasure, 2012). These nuances in the function of developmental cues need to be carefully considered when taking on the challenge of recapitulating them in the in vitro setting.…”