Wnt5a cooperates with canonical Wnts to generate midbrain dopaminergic neurons in vivo and in stem cells

Abstract

Wnts are a family of secreted proteins that regulate multiple steps of neural development and stem cell differentiation.

Prerequisite OCT4 Maintenance Potentiates the Neural Induction of Differentiating Human Embryonic Stem Cells and Induced Pluripotent Stem Cells

“…The hESC-derived NPCs by FGF2 and/or SB431542 treatments are marked with forebrain characteristics and show the multipotent competence to form specific neurons (5,13,43). Canonical Wnt signal is a developmental patterning factor to caudalize anterior neurons and to specialize midbrain neuron formation (2). This Wnt signal in hESC-derived NPCs is antagonized by the endogenous DKK1 expression, and the attenuated Wnt activation consequently renders the establishment of anterior neuroectoderm bias (14).…”

Canonical and noncanonical Wnt signaling in neural stem/progenitor cells

“…While Wnt-3a has been described as canonical, Wnt-5a is generally associated with noncanonical Wnt signaling [49], and Wnt-7a is frequently found to play both canonical and noncanonical roles [50 , 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 51]. Bearing in mind that all these Wnts are required for the correct formation of the nervous system, and also that they often cooperate with one another [52], finetuning of canonical and noncanonical Wnt signals is likely to be necessary for neuronal development. In keeping with this, Wnt1/5a double KO (DKO) mice show exacerbated loss of dopaminergic neurons, when compared to Wnt5a KO mice, as described by Andersson et al [52].…”

“…Bearing in mind that all these Wnts are required for the correct formation of the nervous system, and also that they often cooperate with one another [52], finetuning of canonical and noncanonical Wnt signals is likely to be necessary for neuronal development. In keeping with this, Wnt1/5a double KO (DKO) mice show exacerbated loss of dopaminergic neurons, when compared to Wnt5a KO mice, as described by Andersson et al [52]. This elegant study also showed that mouse stem cells treated with both Wnt-3a and Wnt-5a produced more dopaminergic neurons, than cells treated with a single Wnt, providing further evidence for cooperation between noncanonical and canonical Wnts during dopaminergic differentiation, as suggested in an earlier study by the same group [53].…”

“…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].…”

Animal Models of Parkinson's Disease: A Gateway to Therapeutics?

“…Nurr1 is a potential susceptibility gene for PD [166]. All these observations led to the hypothesis that activating Nurr1 in degenerating DA neurons might delay or modify the disease progression [167]. A synthetic low molecular weight Nurr1 activator named SH1, which increases the transcription of Nurr1, has been tested in a lactacystin-induced nigro-striatal degeneration model in mice [60].…”