Advances in the Signaling Pathways Downstream of Glial-Scar Axon Growth Inhibitors

Abstract

Axon growth inhibitors generated by reactive glial scars play an important role in failure of axon regeneration after CNS injury in mature mammals. Among the inhibitory factors, chondroitin sulfate proteoglycans (CSPGs) are potent suppressors of axon regeneration and are important molecular targets for designing effective therapies for traumatic brain injury or spinal cord injury (SCI). CSPGs bind with high affinity to several transmembrane receptors, including two members of the leukocyte common antigen related (LAR) subfamily of receptor protein tyrosine phosphatases (RPTPs). Recent studies demonstrate that multiple intracellular signaling pathways downstream of these two RPTPs mediate the growth-inhibitory actions of CSPGs. A better understanding of these signaling pathways may facilitate development of new and effective therapies for CNS disorders characterized by axonal disconnections. This review will focus on recent advances in the downstream signaling pathways of scar-mediated inhibition and their potential as the molecular targets for CNS repair.

RhoA drives actin compaction to restrict axon regeneration and astrocyte reactivity after CNS injury

“…Controlling axon regeneration: From extracellular inhibitory factors down to the effector RhoA has been proposed to be a point of convergence that transduces extracellular inhibition to intracellular processes to limit axon regeneration. However, even though numerous RhoA downstream effectors have been identified (Fujita and Yamashita, 2014;Sami et al, 2020), the physiologically relevant effectors have remained unclear. Here we deciphered how neuronal RhoA relays extracellular inhibitory signaling to prevent axon regeneration by acting on the cytoskeleton.…”

“…The small GTPase ras homolog gene family member A (RhoA) is a node onto which extracellular inhibitory signals, including chondroitin sulfate proteoglycans (CSPGs) and CNS myelin, converge (Boueid et al, 2020;Hu and Selzer, 2017;Sami et al, 2020). However, the effector mechanisms that ultimately mediate axon growth restraint have remained undefined (Geoffroy and Zheng, 2014;Sami et al, 2020).…”

“…The small GTPase ras homolog gene family member A (RhoA) is a node onto which extracellular inhibitory signals, including chondroitin sulfate proteoglycans (CSPGs) and CNS myelin, converge (Boueid et al, 2020;Hu and Selzer, 2017;Sami et al, 2020). However, the effector mechanisms that ultimately mediate axon growth restraint have remained undefined (Geoffroy and Zheng, 2014;Sami et al, 2020). One reason for this is that manipulation of RhoA by non-endogenous compounds or by overexpression of its mutant forms leads to stimulation of additional signaling pathways; for example, by scavenging guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) of other Rho GTPases (Pertz, 2010), activating a myriad of additional RhoA-independent effectors.…”

Emerging Exosomes and Exosomal MiRNAs in Spinal Cord Injury

“…Following SCI, myelin fragments and extracellular matrix in the injured area can secrete a series of inhibitors of nerve regeneration to inhibit the self-repair of spinal cord, this limiting the repair effect. Among them, myelin-associated glycoprotein can inhibit neurogenesis and induce axon growth bundle retraction (Jurynczyk et al, 2019), oligodendrocyteassociated myelin glycoprotein can inhibit neurogenesis and stump regeneration (Reindl and Waters, 2019), and CSPG can limit axon plasticity and remyelination (Sami et al, 2020).…”

Water Treadmill Training Ameliorates Neurite Outgrowth Inhibition Associated With NGR/RhoA/ROCK by Inhibiting Astrocyte Activation Following Spinal Cord Injury

“…Nogo receptor 1 (NGR1) and NGR3 are two receptors of myelin-related inhibitors [9]. When these receptors interact with CSPG, they activate the Rho/ROCK signalling pathway and induce the collapse of axonal growth cones [10]. Rho family proteins are a group of guanosine triphosphate-binding proteins with relative molecular weights of approximately 20 ~ 30 kDa.…”