Wnt-Ryk Signaling Mediates Axon Growth Inhibition and Limits Functional Recovery after Spinal Cord Injury

Abstract

Wnt proteins are a large family of diffusible factors that play important roles in embryonic development, including axis patterning, cell fate specification, proliferation, and axon development. It was recently demonstrated that Ryk (receptor related to tyrosine kinase) is a conserved high-affinity Wnt receptor, and that Ryk-Wnt interactions guide corticospinal axons down the spinal cord during development. Here, we report that the Ryk-Wnt signal mediates the inhibition of corticospinal axon growth in the adult spinal cord. The expression of Wnt-5a is induced in reactive astrocytes around the injury site following a spinal cord injury. In vitro, Wnt-5a inhibits the neurite growth of postnatal cerebellar neurons by activating RhoA/Rho-kinase. In rats with thoracic spinal cord contusion, intrathecal administration of a neutralizing antibody to Ryk resulted in significant axonal growth of the corticospinal tract and enhanced functional recovery. Thus, reexpression of the embryonic repulsive cues in adult tissues contributes to the failure of axon regeneration in the central nervous system.

The Ryk Receptor Is Expressed in Glial and Fibronectin-Expressing Cells after Spinal Cord Injury

“…[3][4][5] A growing body of evidence suggests that Wnt signalling may be involved in homeostasis and disease progression in adult tissues, [6][7][8][9][10][11] including the spinal cord. 10,[12][13][14][15][16] Consistent with these findings, we have previously shown that most of Wnt ligands and inhibitors are expressed in the adult spinal cord of rats and, following SCI, are differentially induced with at least Wnt/b-catenin signalling activation in cells that appear to be involved in glial scarring. 13 Strategies seeking to modulate Wnt-dependent signaling pathways have been shown to be beneficial in different experimental models of CNS disorders 8,[17][18][19][20][21][22][23] including SCI.…”

“…13 Strategies seeking to modulate Wnt-dependent signaling pathways have been shown to be beneficial in different experimental models of CNS disorders 8,[17][18][19][20][21][22][23] including SCI. 10,14,24 Ryk is a well-known unconventional Wnt receptor 25 that is composed of a Wnt inhibitory factor 1 (WIF1)-like extracellular domain that enables its interaction with different Wnt ligands. This is in addition to an intracellular domain that is catalytically inactive because of specific amino acid substitutions, 26 although Ryk receptor is known to transduce extracellular signals across the plasma membrane through several mechanisms.…”

“…34 Given the developmental role of Ryk as an essential regulator of axonal growth and the importance of this process in functional recovery following SCI, several studies have investigated the potential of this receptor to mediate axonal regeneration in experimental models of this neuropathological condition. 10,14 Blockage of Ryk activity, which is expressed by corticospinal axons, via intrathecal administration of a Ryk-neutralizing antibody, resulted in a significant growth of axons in the CST and enhanced functional recovery following SCI. 10,14 This strongly suggests that Ryk influences the progression of SCI, and that modulation of Ryk activity may improve functional recovery.…”

“…10,14 Blockage of Ryk activity, which is expressed by corticospinal axons, via intrathecal administration of a Ryk-neutralizing antibody, resulted in a significant growth of axons in the CST and enhanced functional recovery following SCI. 10,14 This strongly suggests that Ryk influences the progression of SCI, and that modulation of Ryk activity may improve functional recovery.…”

Axon Guidance Molecules and Neural Circuit Remodeling After Spinal Cord Injury

“…The corticospinal tract has proven reticent to nearly all experimental attempts to promote long-distance regeneration, though it has been shown to be capable of spontaneous short-range sprouting [85,86]. However, this sprouting is limited by the re-induction of Ryk expression within the lesioned corticospinal axons [75,87]. During development, Ryk expressing corticospinal axons encounter a decreasing gradient of Wnts that propels them caudally; meanwhile, injured corticospinal axons face an abrupt barrier of expressed Wnts surrounding the injury site (Fig.…”