After injury, regenerating axons must grow large distances to reestablish the neural circuitry needed for a functional recovery.  Our objective is to assess whether a mechanism that controls the rate of axon growth during development, can be manipulated to increase the rate of axon regeneration in adults after injury and enhance functional recovery. 

After injury, peripheral nerves must regenerate over considerable distances in adult patients.  This process occurs at sufficiently low speeds (1 mm/day), that denervated targets can atrophy, resulting in loss of motor and sensory function.  Our previous studies have found that “temporal” guidance signals act through the cofilin/Limk1 pathway to control the rate of actin polymerization, and thereby regulate the speed of axon outgrowth.   Increasing cofilin activity, by inactivating its negative regulator Limk1, accelerates the rate of commissural axon extension in the developing spinal cord.  We assessed whether this mechanism could be used in adult mice to increase the rate of regeneration after peripheral nerve injury.

The sciatic nerves of wildtype and Limk1 mutant mice were crushed and analyzed at various time points using immunohistochemistry to assess Wallerian degeneration, macrophage infiltration, regeneration, and cofilin levels.  Behavioral tests were performed to assess recovery of motor and sensory function. 

Cofilin activity dramatically decreased after peripheral nerve injury in a Limk1 dependent manner. Increasing cofilin activity, through the loss of Limk1, promoted axon regrowth after injury as compared to wildtype mice.  The increase in regenerative axon growth also resulted in faster recovery of motor and sensory function.

In this study, we demonstrate that the cofilin/Limk1 pathway regulates the endogenous process of axon regeneration in adult mice. The ability to accelerate axon regeneration offers the promise of significantly reducing painful recovery time for patients and permitting damaged nerves to reconnect with their synaptic targets before atrophy occurs.