Department of Physiology and Biophysics.
Department of Urology.
JCI Insight. 2021 May 10;6(9):138484. doi: 10.1172/jci.insight.138484.
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.
微管（MT）细胞骨架在轴突生长和导向中起着关键作用。在这里，我们确定微管切割酶 fidgetin-like 2（FL2）是轴突再生的负调节剂，也是促进损伤后神经再生的治疗靶点。在培养的成年背根神经节神经元中，FL2 的基因敲除导致轴突更长，并且对抑制性分子的生长锥回缩减弱。鉴于 FL2 耗竭在体外具有促进轴突生长的作用，我们测试了 FL2 是否可以靶向以促进海绵体神经（CN）损伤的啮齿动物模型中的再生。CN 是调节阴茎血流的副交感神经，在根治性前列腺切除术（RP）中经常受损，导致勃起功能障碍（ED）。CN 损伤后应用 FL2-siRNA 可显著增强功能神经恢复。值得注意的是，在双侧神经横断后，在接受 FL2-siRNA 治疗的 8 只动物中有 7 只观察到可见和功能性神经再生，而没有接受对照治疗的动物没有观察到再生。这些研究表明，FL2 是增强周围神经损伤后再生和减轻 RP 后神经源性 ED 的有前途的治疗靶点 - 目前，这种情况只有较差的治疗选择。
