Brain‐derived neurotrophic factor stimulates proliferation and differentiation of neural stem cells, possibly by triggering the Wnt/β‐catenin signaling pathway

Abstract

Brain-derived neurotrophic factor (BDNF) has critical functions in promoting survival, expansion, and differentiation of neural stem cells (NSCs), but its downstream regulation mechanism is still not fully understood. The role of BDNF in proliferation and differentiation of NSCs through Wnt/β-catenin signaling was studied via cell culture of cortical NSCs, Western blotting, immunocytochemistry, and TOPgal (Wnt reporter) analysis in mice. First, BDNF stimulated NSC proliferation dose dependently in cultured neurospheres that exhibited BrdU incorporation and neuronal and glial differentiation abilities. Second, BDNF effectively enhanced cell commitment to neuronal and oligodendrocytic fates, as indicated by increased differentiation marker Tuj-1 (neuronal marker), CNPase (oligodendrocyte marker), and neuronal process extension. Third, BDNF upregulated expression of Wnt/β-catenin signaling (Wnt1 and free β-catenin) molecules. Moreover, these promoting effects were significantly inhibited by application of IWR1, a Wnt signaling-specific blocker in culture. The TOPgal mouse experiment further confirmed BDNF-triggered Wnt signaling activation by β-gal labeling. Finally, an MEK inhibition experiment showed a mediating role of the microtubule-associated protein kinase pathway in BDNF-triggered Wnt/β-catenin signaling cascades. This study overall has revealed that BDNF might contribute to proliferation and neuronal and oligodendrocytic differentiation of NSCs in vitro, most possibly by triggering the Wnt/β-catenin signaling pathway. Nevertheless, determining the exact cross-talk points at which BDNF might stimulate Wnt/β-catenin signaling pathway in NSC activity requires further investigation.

Enhanced selective gene delivery to neural stem cells in vivo by an adeno-associated viral variant

“…These data suggest that the Wnt pathway functions through both proliferation and differentiation mechanisms to induce neurogenesis, consistent with reports that propose a proliferative and a differentiative role (Ashton et al, 2012;Chen et al, 2013;Israsena et al, 2004;Otero et al, 2004). In addition, this study establishes proof-of-principle that AAV r3.45 can be used to deliver transgenes to study NSC regulation in the hippocampus.…”

“…Using AAV r3.45 to deliver CA β-catenin to mouse NSCs in vivo enabled the study of these pathways. Analysis showed significant increases in the number of infected NSCs, neural progenitor cells and neurons, suggesting that the Wnt pathway functions through both proliferation and differentiation mechanisms to induce neurogenesis, consistent with reports demonstrating each role (Ashton et al, 2012;Chen et al, 2013;Israsena et al, 2004;Otero et al, 2004).…”

The Role of Wnt/β-Catenin Signaling Pathway in Disrupted Hippocampal Neurogenesis of Temporal Lobe Epilepsy: A Potential Therapeutic Target?

“…Several regulators might exert their function through a crosstalk link with Wnt signaling. For example, Chen et al [94] used neural stem cell cultures to show induction of BDNF-stimulated cell proliferation and differentiation by triggering the Wnt/b-catenin signaling in vitro. Recently, increasing evidence has shown the critical role of Wnt/b-catenin signaling in epileptogenesis.…”

Quantitative Expression Analysis of Functional Genes in Four Dog Breeds

“…Joubert syndrome is a rare genetic disorder that affects the cerebellum, an area of the brain that controls balance and coordination [31,32]. Wnt signaling pathway controlled by WNT1, is stimulated by BDNF (Brain-derived neurotrophic factor), then induce the proliferation and differentiation of neural stem cells [13]. These genes same expression patterns have crucial roles in brain, and each gene pathway studies will be performed as further studies.…”

“…WNT1 gene is included in all GO terms, and crucial factor of each network structure. WNT1 regulate the wnt signaling pathway, then induce neural stem cell differentiation [13].…”