As discussed in my book on nerve regeneration, inhibition of the RhoA GTPase is a promising approach to promote axonal growth if the blockade of RhoA is restricted to neurons. In contrast, inhibition of RhoA in the glia of the central nervous system (CNS), the astrocytes, prevents axonal regeneration after spinal cord injury.
Inhibitory proteins, e.g. the myelin-associated glycoproteins (MAGs) or the scar-forming proteoglycans (CSPGs) inhibit axonal growth by activating the Rho/ROCK signalling pathway, which prevents the formation of actin filaments in the growth cone and leads to its collapse. However, pharmacological inhibition of RhoA by C3 or of ROCK by fasudil leads to undesirable effects in non-neuronal cells, at least in the CNS.
In a study published last year by Jingmin Liu and Xinrui Ma in Glia, it was shown that the elimination of RhoA in Schwann cells, i.e. in peripheral glial cells, can actually promote regeneration after nerve injury in the PNS. To this end, they used two strains of Schwann cell-specific RhoA knockout mice (conditional KO mice).
The results showed that Schwann cell transdifferentiation appears to be the main mechanism underlying the enhanced nerve regeneration in Schwann cell RhoA KO mice, as in these animals Wallerian axon degeneration is promoted in a JNK-dependent manner and there is an increased release of neurotrophic factors (especially NT-3, NGF, BDNF and GDNF). This enhances axonal growth and re-myelination after sciatic nerve injury, leading to faster transmission of action potentials, improved walking movements and reduced muscle atrophy.
Taken together, the new findings emphasise that cell-specific targeting of RhoA may represent a novel and effective approach to promote axonal regeneration in the nervous system.
Reference:
Liu J, Ma X, Hu X, Wen J, Zhang H, Xu J, He Y, Wang X, Guo J (2023) Schwann cell-specific RhoA knockout accelerates peripheral nerve regeneration via promoting Schwann cell dedifferentiation. Glia 71:1715
Image credit: Fig. 1.22 from Klimaschewski L.P. The regeneration of nerves and spinal cord. Springer, 2023