Targeting a Dominant Negative Rho Kinase to Neurons Promotes Axonal Outgrowth and Partial Functional Recovery After Rat Rubrospinal Tract Lesion

The study investigates whether blocking the RhoA-ROCK signal pathway, known to inhibit axon regeneration after CNS injury, can promote axon outgrowth and functional recovery. This was achieved by neuron-specific expression of a dominant negative mutant of ROCK (DNROCK) using lentiviral vectors. In vitro experiments showed that DNROCK-expressing neurons had a greater chance of generating neurites and longer neurites compared to control neurons when seeded on myelin proteins, which are known inhibitors of axon growth. In vivo experiments involved injecting lentiviruses into the red nucleus of adult rats, followed by transection of the rubrospinal tract (RST). The DNROCK group exhibited better functional recovery in both hindlimbs and forelimbs compared to the control group, with more RST axons growing to the spinal cord caudal to the lesion.

• 1
  DNROCK expression in DRG neurons promotes neurite growth on myelin proteins in vitro, overcoming the inhibitory effects of CNS myelin.
• 2
  Inhibition of ROCK by DNROCK reduces myelin-induced phosphorylation of CRMP2 at growth cones, a key mediator of growth cone collapse.
• 3
  In vivo, DNROCK promotes axonal outgrowth of axotomized RST, leading to more axons growing around and beyond the lesion site.