Wnt-3a and Wnt-3 differently stimulate proliferation and neurogenesis of spinal neural precursors and promote neurite outgrowth by canonical signaling

Wnt factors regulate neural stem cell development and neuronal connectivity. Here we investigated whether Wnt-3a and Wnt-3, expressed in the developing spinal cord, regulate proliferation and the neuronal differentiation of spinal cord neural precursors (SCNP). Wnt-3a promoted a sustained increase of SCNP proliferation, whereas Wnt-3 enhanced SCNP proliferation transiently and increased neurogenesis through β-catenin signaling. Consistent with this, Wnt-3a and Wnt-3 differently regulate the expression of Cyclin-dependent kinase inhibitors. Furthermore, Wnt-3a and Wnt-3 stimulated neurite outgrowth in SCNP-derived neurons through ß-catenin and TCF4-dependent transcription. GSK-3ß inhibitors mimicked Wnt signaling and promoted neurite outgrowth in established cultures. We conclude that Wnt-3a and Wnt-3 signal through the canonical Wnt/β-catenin pathway to regulate different aspects of SCNP development. These findings may be of therapeutic interest for the treatment of neurodegenerative diseases and nerve injury.