Wnt Signaling Regulates Multipolar-to-Bipolar Transition of Migrating Neurons in the Cerebral Cortex

Abstract

The precise timing of pyramidal cell migration from the ventricular germinal zone to the cortical plate is essential for establishing cortical layers, and migration errors can lead to neurodevelopmental disorders underlying psychiatric and neurological diseases. Here, we report that Wnt canonical as well as non-canonical signaling is active in pyramidal precursors during radial migration. We demonstrate using constitutive and conditional genetic strategies that transient downregulation of canonical Wnt/β-catenin signaling during the multipolar stage plays a critical role in polarizing and orienting cells for radial migration. In addition, we show that reduced canonical Wnt signaling is triggered cell autonomously by time-dependent expression of Wnt5A and activation of non-canonical signaling. We identify ephrin-B1 as a canonical Wnt-signaling-regulated target in control of the multipolar-to-bipolar switch. These findings highlight the critical role of Wnt signaling activity in neuronal positioning during cortical development.

Valproic acid exposure sequentially activates Wnt and mTOR pathways in rats

“…3D and F). Consistent with previous studies (Boitard et al, 2015) , the expression of β-catenin was found in both neuron and astrocyte cells (Fig. S2B).…”

Progenitor Hyperpolarization Regulates the Sequential Generation of Neuronal Subtypes in the Developing Neocortex

“…We first used a reporter construct to monitor β-catenin-dependent WNT activity (Boitard et al, 2015), which confirmed that WNT signaling decreases as corticogenesis proceeds. Supporting an action of the V m in this process, E14.5 AP hyperpolarization with Kir2.1 decreased canonical WNT signaling to levels normally found at E15.5 (Figure 7A).…”

“…Hyperpolarization of E14.5 APs decreases neuronal production to levels normally found at E15.5 (Figure 6A); using a dominant-negative TCF construct (DN-TCF) to repress WNT signalling, we observed a similar effect, in line with previous findings (Munji et al, 2011) (Figure 7B). Furthermore, constitutive WNT activation using β-catenin overexpression (Boitard et al, 2015) mitigated the effect of hyperpolarization (Figure 7B), demonstrating that WNT acts as a molecular link between V m and neurogenesis.…”

Wnt5a is essential for hippocampal dendritic maintenance and spatial learning and memory in adult mice

“…That prominent hippocampal Wnt5a expression is detected only at postnatal stages was intriguing, given the reported roles of Wnt5a in embryonic processes in the brain (15,(22)(23)(24)(25). Wnt5a expression in the postnatal hippocampus, together with evidence supporting the role of Wnts in regulating morphological changes in cultured hippocampal neurons (26,27), prompted us to address the functions of Wnt5a in hippocampal neurons in vivo.…”