Ectopic Wnt/Beta–Catenin Signaling Induces Neurogenesis in the Spinal Cord and Hindbrain Floor Plate

Abstract

The most ventral structure of the developing neural tube, the floor plate (FP), differs in neurogenic capacity along the neuraxis. The FP is largely non-neurogenic at the hindbrain and spinal cord levels, but generates large numbers of dopamine (mDA) neurons at the midbrain levels. Wnt1, and other Wnts are expressed in the ventral midbrain, and Wnt/beta catenin signaling can at least in part account for the difference in neurogenic capacity of the FP between midbrain and hindbrain levels. To further develop the hypothesis that canonical Wnt signaling promotes mDA specification and FP neurogenesis, we have generated a model wherein beta–catenin is conditionally stabilized throughout the FP. Here, we unambiguously show by fate mapping FP cells in this mutant, that the hindbrain and spinal cord FP are rendered highly neurogenic, producing large numbers of neurons. We reveal that a neurogenic hindbrain FP results in the altered settling pattern of neighboring precerebellar neuronal clusters. Moreover, in this mutant, mDA progenitor markers are induced throughout the rostrocaudal axis of the hindbrain FP, although TH+ mDA neurons are produced only in the rostral aspect of rhombomere (r)1. This is, at least in part, due to depressed Lmx1b levels by Wnt/beta catenin signaling; indeed, when Lmx1b levels are restored in this mutant, mDA are observed not only in rostral r1, but also at more caudal axial levels in the hindbrain, but not in the spinal cord. Taken together, these data elucidate both patterning and neurogenic functions of Wnt/beta catenin signaling in the FP, and thereby add to our understanding of the molecular logic of mDA specification and neurogenesis.

A rare WNT1 missense variant overrepresented in ASD leads to increased Wnt signal pathway activation

“…In animal models, hyperactivation of Wnt/β-catenin signaling can lead to dominant neurodevelopmental defects including in brain regionalization, 42, 43 neural precursor proliferation, cell fate specification, neuron migration, 44, 45, 46, 47 and in dendrite and synapse formation or function. 48, 49 A mutation in a gene, such as WNT1 , that modestly increases activation of this downstream signaling pathway would therefore be expected to result in neurodevelopmental and behavioral phenotypes.…”

Mesodiencephalic Dopaminergic Neuronal Differentiation Does Not Involve GLI2A-Mediated SHH-Signaling and Is under the Direct Influence of Canonical WNT Signaling

“…Several reports have suggested that WNT-signaling is critical for the development of the mdDA system [19], [38], [39]. The WNT-family is a large protein family, and although several members are known to be expressed in the mouse embryonic midbrain, not much is known about the function of these WNTs.…”

Roles of Wnt/β-Catenin Signaling in Retinal Neuron-Like Differentiation of Bone Marrow Mesenchymal Stem Cells from Nonobese Diabetic Mice

“…Some recent studies have shown that Wnt/β-catenin signaling is involved in differentiation into neuron-like cells (Sánchez-Sánchez et al 2010; Salero and Hatten 2007; Otero et al 2004; Kuwabara et al 2009; Joksimovic et al 2012; Wei et al 2012). To identify the expression of Wnt/β-catenin signaling in NOD-MSCs, the β-catenin and phosphorylated β-catenin expressions in the NOD-MSCs and ICR-MSCs were examined by Western blot analysis.…”

“…Neural crest progenitor cells were shown to acquire Brn3a expression at the expense of Sox10 expression by Wnt/β-catenin signaling (Hari et al 2002; Lee et al 2004a). Furthermore, accumulating studies have indicated that Wnt/β-catenin signaling has also been shown to promote neuronal differentiation from embryonic, somatic, and neural stem cells or progenitors (Sánchez-Sánchez et al 2010; Salero and Hatten 2007; Otero et al 2004; Kuwabara et al 2009; Joksimovic etal. 2012; Wei etal.…”