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

Abstract

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 and decreased the expression of cyclin-dependent kinase inhibitors. In contrast, Wnt-3 transiently enhanced SCNP proliferation and increased neurogenesis through β-catenin signaling. Furthermore, both Wnt-3a and Wnt-3 stimulated neurite outgrowth in SCNP-derived neurons through β-catenin- and TCF4-dependent transcription. Glycogen synthase kinase-3β inhibitors mimicked Wnt signaling and promoted neurite outgrowth in established cultures. We conclude that Wnt-3a and Wnt-3 factors 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.

Wnt signaling promotes axonal regeneration following optic nerve injury in the mouse

“…To our knowledge, this is the first study showing that Wnt signaling promotes both neuronal survival and regeneration of CNS axons following an axonal injury. Our findings are consistent with previous studies that showed a neuroprotective role for Wnt signaling in the RGCs following neuronal insults, such as excitotoxicity (Seitz et al, 2010), and an axonal growth role for Wnt within the adult spinal cord and sensory neurons after injury (Liu et al, 2008, Hollis and Zou, 2012) (Yin et al, 2008, David et al, 2010). …”

“…Also, Wnt3a may directly regulate growth cone remodeling by altering microtubule stability through differential binding of its downstream components, APC and Dvl1, to the positive ends of microtubules (Purro et al, 2008). Wnt signaling has also been shown to promote axonal growth within the adult spinal cord and sensory neurons after injury (Liu et al, 2008, Hollis and Zou, 2012) (Yin et al, 2008, David et al, 2010), and Wnt signaling regulates astrogliosis and radial glial neurogenesis during axon regeneration following CNS injury (Duncan et al, 2014, Briona et al, 2015). Wnt signaling is known to regulate inflammatory signaling, which has reparative and pro-regenerative effects (Marchetti and Pluchino, 2013).…”

Activated β-catenin Forces N2A Cell-derived Neurons Back to Tumor-like Neuroblasts and Positively Correlates with a Risk for Human Neuroblastoma

“…1-3). Combining these results with previous reports 19-20, we suggest that Wnt/β-catenin signaling have distinct functions in different processes and different physiological conditions of neuronal differentiating. Here, our results reveal a novel function of Wnt/β-catenin pathway in N2A cell-derived neuron cell fate modulation and imply the relationship of β-catenin-mediated activation and neuroblastoma formation.…”

“…In previous studies, the Wnt signaling pathway has been demonstrated to participate in many normal and abnormal biological processes 16. During neural development, Wnt/β-catenin signaling pathway takes part in neural crest formation 17-18, neuronal differentiation as well as neurite outgrowth during cultured early-born hippocampus neuron differentiation 19-20. In this study, we first promoted N2A cells to differentiate into neurons (differentiation for 4 days in serum-free medium), then activated Wnt/β-catenin signaling in these N2A cell-derived neurons and found that activated Wnt/β-catenin signaling forced these N2A cell-differentiated neurons to become tumor-like neuroblasts (Figs.…”

Transcriptional and Post-Transcriptional Regulation of SPAST, the Gene Most Frequently Mutated in Hereditary Spastic Paraplegia

“…Intriguingly, recent studies have shown that the Drosophila ortholog of NRF1, Erect Wing (EWG), interacts with an Armadillo/β-catenin-TCF complex at specific chromatin sites and promotes Wnt/Wingless signaling in neurons and flight muscle development [57]. Consistent with roles in a common pathway, neurite outgrowth is induced by Wnt signaling [58]–[61], SOX11 [43], [51], [62], NRF1 [63], and spastin [25], [64]. Furthermore, Wnt signaling is involved in guidance of corticospinal axons that descend from the motor cortex and cross the midline into and down the spinal cord [59].…”