Fidgetin-like 2 negatively regulates axonal growth and can be targeted to promote functional nerve regeneration
Lisa Baker, Moses Tar, Adam H. Kramer, Guillermo A. Villegas, Rabab A. Charafeddine, Olga Vafaeva, Parimala Nacharaju, Joel Friedman, Kelvin P. Davies, David J. Sharp
Lisa Baker, Moses Tar, Adam H. Kramer, Guillermo A. Villegas, Rabab A. Charafeddine, Olga Vafaeva, Parimala Nacharaju, Joel Friedman, Kelvin P. Davies, David J. Sharp
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Research Article Neuroscience Reproductive biology

Fidgetin-like 2 negatively regulates axonal growth and can be targeted to promote functional nerve regeneration

Abstract

The microtubule (MT) cytoskeleton plays a critical role in axon growth and guidance. Here, we identify the MT-severing enzyme fidgetin-like 2 (FL2) as a negative regulator of axon regeneration and a therapeutic target for promoting nerve regeneration after injury. Genetic knockout of FL2 in cultured adult dorsal root ganglion neurons resulted in longer axons and attenuated growth cone retraction in response to inhibitory molecules. Given the axonal growth-promoting effects of FL2 depletion in vitro, we tested whether FL2 could be targeted to promote regeneration in a rodent model of cavernous nerve (CN) injury. The CNs are parasympathetic nerves that regulate blood flow to the penis, which are commonly damaged during radical prostatectomy (RP), resulting in erectile dysfunction (ED). Application of FL2-siRNA after CN injury significantly enhanced functional nerve recovery. Remarkably, following bilateral nerve transection, visible and functional nerve regeneration was observed in 7 out of 8 animals treated with FL2-siRNA, while no control-treated animals exhibited regeneration. These studies identify FL2 as a promising therapeutic target for enhancing regeneration after peripheral nerve injury and for mitigating neurogenic ED after RP — a condition for which, at present, only poor treatment options exist.

Authors

Lisa Baker, Moses Tar, Adam H. Kramer, Guillermo A. Villegas, Rabab A. Charafeddine, Olga Vafaeva, Parimala Nacharaju, Joel Friedman, Kelvin P. Davies, David J. Sharp

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Figure 6

Application of FL2-siRNA after bilateral CN transection leads to visible regeneration and partial recovery of erectile function.

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Application of FL2-siRNA after bilateral CN transection leads to visible...
(A) Image of siRNA wafer prior to application. Scale bar: 0.5 cm. (B) Relative levels of FL2 mRNA in the MPG 2 weeks after CN transection and wafer treatment, normalized to ribosomal protein L19 (RPL19) (unpaired 2-tailed Student’s t test, P = 0.08, n = 5). (C) Images of the CN prior to transection (i); immediately after transection (ii); and 2 weeks after transection and con-siRNA or FL2-siRNA wafer treatment (iii and iv, respectively). (D) Mean maximal ICP/BP measurements following different levels of stimulation of transected/siRNA wafer–treated animals and naive age-matched controls (mean ± SEM). Note control-siRNA wafer transected nerves could not be stimulated due to the degree of retraction of the severed nerve segments; therefore only baseline ICP/BP is shown.