A dynamic gradient of Wnt signaling controls initiation of neurogenesis in the mammalian cortex and cellular specification in the hippocampus

Abstract

Neurogenesis in the developing neocortex is a strictly regulated process of cell division and differentiation. Here we report that a gradual retreat of canonical Wnt signaling in the cortex from lateral-to-medial and anterior-to-posterior is a prerequisite of neurogenesis. Ectopic expression of a beta-catenin/LEF1 fusion protein maintains active canonical Wnt signaling in the developing cortex and delays the expression onset of the neurogenic factors Pax6, Ngn2 and Tbr2 and subsequent neurogenesis. Contrary to this, conditional ablation of beta-catenin accelerates expression of the same neurogenic genes. Furthermore, we show that a sustained canonical Wnt activity in the lateral cortex gives rise to cells with hippocampal characteristics in the cortical plate at the expense of the cortical fate, and to cells with dentate gyrus characteristics in the hippocampus. This suggests that the dose of canonical Wnt signaling determines cellular fate in the developing cortex and hippocampus, and that recession of Wnt signaling acts as a morphogenetic gradient regulating neurogenesis in the cortex.

Effect of canonical Wnt inhibition in the neurogenic cortex, hippocampus, and premigratory dentate gyrus progenitor pool

“…Along this line, failure to develop a proper DG in the LRP6 or Lef1 mutants where compensation may occur with Lrp5 or TCFs, respectively, the compensation may not be sufficient for development of DG progenitor cells but strong enough for hippocampal layers. This "gradient" hypothesis is in agreement with the analysis of D6-CLEF mice in which ectopic activation of the Wnt pathway led to over proliferation and altered cellular specification in the cortex where Prox1 ϩ ectopic cells required a higher level of Wnts than hippocampal specific cells (Machon et al, 2007).…”

“…2E-EЈ,F-FЈ). This is not surprising because canonical Wnt signaling is naturally down-regulated in this area in a gradual movement to initiate a neurogenic program in the cortex (Machon et al, 2007). The presence of intact adherens junctions shows that Dkk1 does not affect the cytoplasmic role of ␤-catenin in the cytoskeleton.…”

“…Recently, it has been reported that the canonical Wnt pathway is also important for cellular proliferation in the ventricular zone and for fate determination in the cortex (Chenn and Walsh, 2002;Backman et al, 2005;Zhou et al, 2006;Woodhead et al, 2006;Machon et al, 2007). Furthermore, it was recently shown that neurogenesis in the cortex is directly correlated with a gradual decrease of canonical Wnt signaling (Machon et al, 2007;Faedo et al, 2007).…”

Canonical and noncanonical Wnt signaling in neural stem/progenitor cells

“…Loss of PAX6 expression is not followed by expression of Tbr2, indicating that differentiation is impaired [108]. In keeping with these findings, conditional ablation of β-catenin accelerates expression of the previously mentioned neurogenic genes in a different study [109], and stabilization of Axin by the tankyrase inhibitor IWR-1 (which prevents β-catenin from signaling) reduces NSC proliferation in cortical neurospheres [110]. Thus, the importance of Wnt/β-catenin signaling may lie in its role in maintaining neural stem/progenitor cell proliferation.…”

Genome-wide survey implicates the influence of copy number variants (CNVs) in the development of early-onset bipolar disorder

“…The 10q11 microduplication (Figure 1a) 37,38 which is known to regulate neurogenesis and neuroprotection.…”