Wnt/ß-catenin signaling is required for radial glial neurogenesis following spinal cord injury

Abstract

Spinal cord injury results in permanent sensorimotor loss in mammals, in part due to a lack of injury-induced neurogenesis. The regeneration of neurons depends upon resident neural progenitors, which in zebrafish persist throughout the central nervous system as radial glia. However the molecular mechanisms regulating spinal cord progenitors remain uncharacterized. Wnt/ß-catenin signaling is necessary for the regenerative response of multiple tissues in zebrafish as well as other vertebrates, but it is not known whether the pathway has a role in spinal cord regeneration. Here we show that spinal radial glia exhibit Wnt/ß-catenin activity as they undergo neurogenesis following transection. We then use Cre-mediated lineage tracing to label the progeny of radial glia and show that Wnt/ß-catenin signaling is required for progenitors to differentiate into neurons. Finally, we show that axonal regrowth after injury also requires Wnt/ß-catenin signaling, suggesting coordinated roles for the pathway in functional recovery. Our data thus establish Wnt/ß-catenin pathway activation as a necessary step in spinal cord regeneration.

Wnt signaling controls pro-regenerative Collagen XII in functional spinal cord regeneration in zebrafish

“…2c). These cells have previously been described as glial cells 14 .

Fig. 2Wnt/β-catenin signaling is mainly active in fibroblast-like cells after spinal cord lesion.

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“…Moreover, axonal reconnection, which is necessary for functional recovery in adult 11 and larval zebrafish 12, 13 , also depends on Wnt/β-catenin pathway activity in both systems 14, 15 . Wnt/β-catenin signaling involves extracellular Wnt ligand-induced stabilization and translocation of β-catenin into the nucleus where it modifies target gene transcription together with Tcf/Lef family proteins 16 .…”

Hypothalamic radial glia function as self-renewing neural progenitors in the absence of Wnt/ß-catenin signaling

“…This low activity state could be regulated by extracellular or intracellular pathway antagonists, or radial glia might simply fail to express the appropriate receptors to transduce Wnt signals. Regardless of the mechanism, it appears that this characteristic of hypothalamic radial glia is similar to other radial glial populations in the zebrafish retina and spinal cord (Goldman, 2014;Briona et al, 2015), but differs from radial glia in the mammalian dentate gyrus (Qu et al, 2010). Other studies have similarly shown that neural progenitor populations vary dramatically in their interpretation of pathway activity (Poschl et al, 2013).…”

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

“…Muller glia are generally protective to RGCs (Chong and Martin, 2015), induce RGC neuritogenesis in vitro (Garcia et al, 2002), and viral delivery of CNTF to Muller glia promoted optic nerve axonal extension and sprouting (Pernet et al, 2013a). Therefore, it is possible that Muller glia play a supportive role to RGCs following Wnt stimulation that aids in survival and promotes regeneration, similar to its function in astroglia following spinal cord injury (Duncan et al, 2014, Briona et al, 2015). In contrast, amacrine cells are generally inhibitory to RGC regeneration (Goldberg et al, 2002, Chong and Martin, 2015).…”

“…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).…”