Expression of brain-derived neurotrophic factor is regulated by the Wnt signaling pathway

Brain-derived neurotrophic factor (BDNF) is a well characterized neurotrophin that mediates a wide variety of activities in the central nervous system, including neuronal differentiation, neuroprotection, and synaptic plasticity. The canonical Wnt signaling pathway is a critical regulator of embryonic development and homeostasis in adult tissues. Our group and others recently demonstrated that Wnt signaling induces BDNF expression in neurons and glia. However, the precise relationship between BDNF and Wnt signaling pathways is not understood. Here, we investigated Wnt signaling regulation of BDNF at the transcriptional level using a combination of bioinformatics and molecular analyses. Analysis of the BDNF gene promoter identified seven binding motifs for Wnt-dependent TCF/LEF transcription factors. Furthermore, specific BDNF promoters were induced by the Wnt3a ligand using chloramphenicol acetyl transferase reporter assays and a dominant-negative TCF4 gene reduced Wnt3a-mediated induction. Finally, Wnt3a induced expression of BDNF and other members of the BDNF signaling pathway in glia cells. Therefore, these data indicate that BDNF is a direct target of Wnt signaling, which provides a new insight into the interaction between two essential signaling pathways.