A growing field: The regulation of axonal regeneration by Wnt signaling

Abstract

The canonical Wnt/β-catenin pathway is a highly conserved signaling cascade that plays critical roles during embryogenesis. Wnt ligands regulate axonal extension, growth cone guidance and synaptogenesis throughout the developing central nervous system (CNS). Recently, studies in mammalian and fish model systems have demonstrated that Wnt/β-catenin signaling also promotes axonal regeneration in the adult optic nerve and spinal cord after injury, raising the possibility that Wnt could be developed as a therapeutic strategy. In this review, we summarize experimental evidence that reveals novel roles for Wnt signaling in the injured CNS, and discuss possible mechanisms by which Wnt ligands could overcome molecular barriers inhibiting axonal growth to promote regeneration. A central challenge in the neuroscience field is developing therapeutic strategies that induce robust axonal regeneration. Although adult axons have the capacity to respond to axonal guidance molecules after injury, there are several major obstacles for axonal growth, including extensive neuronal death, glial scars at the injury site, and lack of axonal guidance signals. Research in rodents demonstrated that activation of Wnt/β-catenin signaling in retinal neurons and radial glia induced neuronal survival and axonal growth, but that activation within reactive glia at the injury site promoted proliferation and glial scar formation. Studies in zebrafish spinal cord injury models confirm an axonal regenerative role for Wnt/β-catenin signaling and identified the cell types responsible. Additionally, in vitro and in vivo studies demonstrated that Wnt induces axonal and neurite growth through transcription-dependent effects of its central mediator β-catenin, potentially by inducing regeneration-promoting genes. Canonical Wnt signaling may also function through transcription-independent interactions of β-catenin with cytoskeletal elements, which could stabilize growing axons and control growth cone movement. Therefore, these studies suggest that Wnt-induced pathways responsible for regulating axonal growth during embryogenesis could be repurposed to promote axonal growth after injury.

Wnt/β-Catenin Signaling Pathway Governs a Full Program for Dopaminergic Neuron Survival, Neurorescue and Regeneration in the MPTP Mouse Model of Parkinson’s Disease

“…Hence, high levels of expression of Wnt/β-catenin genes, together with their Wnt-dependent transcription factor, Nurr1, were associated with a remarkable time-dependent nigrostriatal DAergic histopathological and functional neurorestoration upon MPTP injury [80]. These results are in line with earlier and more recent evidence indicating that Wnt/β-catenin signaling is required for radial glial neurogenesis and neuron regeneration following injury [146,147,148]. Hence, using Cre-mediated lineage tracing to label the progeny of radial glia, Wnt/β-catenin activation was necessary for progenitors to differentiate into neurons [147].…”

Role of Macrophages and Microglia in Zebrafish Regeneration

“…Wnt signaling directly affects macrophage proliferation and cytokine release, modulating appendage inflammation and regeneration as well as regulating proliferation after injury in other structures, such as the optic tectum of adult zebrafish [ 87 , 111 ]. These findings suggest that Wnt signaling may play a significant role in the regeneration of different parts of the CNS, including the hypothalamus, retina, and spinal cord [ 119 , 126 , 127 , 128 ].…”

Telomerase increasing compound protects hippocampal neurons from amyloid beta toxicity by enhancing the expression of neurotrophins and plasticity related genes

“…The importance of the Wnt signaling pathway in neurodegenerative disorders may lie in its role in processes such as neurogenesis and regulation of synaptic transmission and plasticity 26 . The functional importance of the Wnt signaling pathway in neuronal growth and plasticity may be due to the expression of neurotrophins such as BDNF, and NGF since their expression is regulated by Wnt 27,28 . A positive reinforcement loop between TERT and Wnt exists in which TERT can function as an activator of the Wnt signaling pathway 29 , while simultaneously being up-regulated by WNT signaling 30 .…”