Neuronal production and precursor proliferation defects in the neocortex of mice with loss of function in the canonical Wnt signaling pathway

Targeting of neurotrophic factors, their receptors, and signaling pathways in the developmental neurotoxicity of organophosphates in vivo and in vitro

“…The wnt family interacts with a set of receptors encoded by the fzd genes [49,86], with signals transduced by the dvl group and negatively modulated by the dkk genes [37]. Importantly for our work, the fgf and wnt families are coexpressed in adjacent locations within the developing brain and deletion of genes from either group produces parallel defects in forebrain development [9,38,66,69,70,100]. As in our earlier work [79], we utilized microarrays to examine the key members of each gene family, comparing similarities and differences in the effects of chlorpyrifos and diazinon: if the involvement of neurotrophic mechanisms is unrelated to the inhibition of cholinesterase, then there are likely to be significant disparities between the two agents.…”

“…Indeed, although they are not classical neurotrophic factors, both sets of genes are critical for normal brain development [16,98] and specifically control the architectural development of the hippocampus and neocortex [32,52,54,70,100], two areas that are known to be targeted for disruption by organophosphates [1,65,72,73,91]. There is limited information linking altered expression of specific members of the wnt and fzd families to adverse neurobehavioral outcomes, but it is notable that wnt5a and fzd3, which we found to be reduced by both chlorpyrifos and diazinon, are key determinants in establishing the dopaminergic phenotype [12] and development of dopamine projections [96].…”

Canonical and noncanonical Wnt signaling in neural stem/progenitor cells

“…Induced proliferation of hESCs/mNSCs [65,66] Recombinant Wnt-3a Induced proliferation and differentiation of hESCs [67] Wnt-4 silencing Impaired early differentiation in hECCs [68] Wnt-5a KO Impaired neurite development in the olfactory bulb (OB) [44] Wnt-1 and Wnt-5a DKO Impaired neurogenesis of midbrain dopaminergic neurons [52] Wnt-5a KO Impaired axon growth and guidance of dopaminergic neurons [45] Wnt-5a CM Increased synaptogenesis and maturation of hippocampal progenitors [69,70] Wnt-5a overexpression Induced axonal differentiation in hippocampal cultures [71] Wnt-7a KO Delayed morphological maturation of glomerular rosettes and synapsin I accumulation [46] Wnt-7a KO Impaired ventral midbrain neurogenesis [47] Wnt-7a and Dvl DKO Defective spine morphogenesis and mossy fiber-CA3 synaptic transmission [48] Wnt-7a Proposed as a key element in the regulation of NSC self-renewal/differentiation; altered spindle- Canonical Wnt receptors are also important for correct neural development (Table 2): FZD3 KO mice show impaired axonal guidance [73] while LRP6 KO mice present cortical defects [74]. Also, FZD1 has been shown to be the receptor for canonical Wnt-1 in mouse tyrosine hydroxylase positive neurons, which activates β-catenin-dependent signaling promoting neuroprotection in dopaminergic neurons [75].…”

“…Disrupted production of dentate granule neurons and radial glial scaffolding in KO mice [104] Cortical defects in KO mice [74] Increased differentiation into DA neurons in KO mESCs [59] Delayed DA neuron differentiation in KO mice [105] overexpression or activation of β-catenin expands the neuronal progenitor pool in the developing brain [106,107], and expression of constitutively active β-catenin under the control of the GFAP promoter results in enlarged ventricles and an initial expansion of the PAX6-positive ventricular zone that is subsequently lost. Loss of PAX6 expression is not followed by expression of Tbr2, indicating that differentiation is impaired [108].…”

WNT Protein-independent Constitutive Nuclear Localization of β-Catenin Protein and Its Low Degradation Rate in Thalamic Neurons

“…The early development of the dorsal thalamus involves activation of proximal steps of the Wnt signaling cascade (9,13). The constitutive accumulation of ␤-catenin in the nuclei of postnatal dorsal thalamic neurons (23,26) suggests the persistent activation of the Wnt pathway in this region of the adult brain.…”