Wnt Signaling Promotes Neuronal Differentiation from Mesenchymal Stem Cells Through Activation of Tlx3

Abstract

Wnt/β-catenin signaling promotes neural differentiation by activation of the neuron-specific transcription factors, Neurogenin1 (Ngn1), NeuroD and Brn3a, in the nervous system. Since neurons in cranial sensory ganglia and dorsal root ganglia transiently express Ngn1, NeuroD and Brn3a during embryonic development, we hypothesized that Wnt proteins could instructively promote a sensory neuronal fate from mesencymal stem cells (MSCs) directed to differentiate into neurons. Consistent with our hypothesis, Wnt1 induced expression of sensory neuron markers including Ngn1, NeuroD and Brn3a, as well as glutamatergic markers in neurally-induced MSCs in vitro and promoted engraftment of transplanted MSCs in the inner ear bearing selective loss of sensory neurons in vivo. Given the consensus function of T cell leukemia 3 (Tlx3), as a glutamatergic selector gene, we postulated that the effects of canonical Wnt signaling on sensory neuron and glutamatergic marker gene expression in MSCs may be mediated by Tlx3. We first confirmed that Wnt1 indeed up-regulates Tlx3 expression, which can be suppressed by canonical Wnt inhibitors. Next, our chromatin immunoprecipitation assays revealed that T-cell factor 3/4 (TCF3/4), Wnt-activated DNA binding proteins, interact with a regulatory region of Tlx3 in MSCs after neural induction. Furthermore, we demonstrated that forced expression of Tlx3 in MSCs induced sensory and glutamatergic neuron markers after neural induction. Together, these results identify Tlx3 as a novel target for canonical Wnt signaling that confers somatic stem cells with a sensory neuron phenotype upon neural induction.

RETRACTED ARTICLE: Mesenchymal stem cells and neural crest stem cells from adult bone marrow: characterization of their surprising similarities and differences

“…A recent publication revealed that Wnt1 factor induces Tlx3 expression, which was correlated with neuronal differentiation ability of MSC [19]. Wnt1 is a developmentally important gene involved in intercellular signaling that is expressed by CGNs in newborn mice [20].…”

Neural Differentiation of Human Umbilical Cord Blood-derived Mesenchymal Stem Cells

“…Previous studies showed that RA combined with other factors, such as NGF, β-ME, BDNF, Forskolin, and IBMX, is necessary for the neural differentiation of MSCs in vitro (29)(30)(31). In the present study, it was found that after the combined treatment with a low concentration of RA, more than 30% of hUCB-MSCs were differentiated into GFAPexpressing cells.…”

β-Catenin, a Transcription Factor Activated by Canonical Wnt Signaling, Is Expressed in Sensory Neurons of Calves Latently Infected with Bovine Herpesvirus 1

“…Canonical Wnt signaling, due to ␤-catenin activation, promotes axonal guidance, neuronal differentiation, neuronal connectivity, and cell survival (33,(59)(60)(61). Combining this knowledge with our previous observations that ORF2 expression stimulates neurite formation in cells expressing Notch (42,43), we tested whether ␤-catenin cooperates with ORF2 to stimulate neurite formation in Neuro-2A cells.…”