Genome-wide study reveals novel roles for formin-2 in axon regeneration as a microtubule dynamics regulator and therapeutic target for nerve repair.

Peripheral nerves regenerate successfully; however, clinical outcome after injury is poor. We demonstrated that low-dose ionizing radiation (LDIR) promoted axon regeneration and function recovery after peripheral nerve injury (PNI). Genome-wide CpG methylation profiling identified LDIR-induced hypermethylation of the Fmn2 promoter, exhibiting injury-induced Fmn2 downregulation in dorsal root ganglia (DRGs). Constitutive knockout or neuronal Fmn2 knockdown accelerated nerve repair and function recovery. Mechanistically, increased microtubule dynamics at growth cones was observed in time-lapse imaging of Fmn2 -deficient DRG neurons. Increased HDAC5 phosphorylation and rapid tubulin deacetylation were found in regenerating axons of neuronal Fmn2 -knockdown mice after injury. Growth-promoting effect of neuronal Fmn2 knockdown was eliminated by pharmaceutical blockade of HDAC5 or neuronal Hdac5 knockdown, suggesting that Fmn2 deletion promotes axon regeneration via microtubule post-translational modification. In silico screening of FDA-approved drugs identified metaxalone, administered either immediately or 24-h post-injury, accelerating function recovery. This work uncovers a novel axon regeneration function of Fmn2 and a small-molecule strategy for PNI. [Display omitted] • LDIR promotes intrinsic axonal growth, function recovery, and Fmn2 hypermethylation • Fmn2 as a regulator of injury response, axon regeneration, and microtubule dynamics • Fmn2 deletion promotes axon regeneration via HDAC5-mediated tubulin deacetylation • FDA drug metaxalone recapitulates growth-promoting effects of Fmn2 deletion for PNI Proximal peripheral nerve injury (PNI) results in poor clinical outcomes. Au et al. reveal that ionizing radiation induces intrinsic growth of injured neurons and Fmn2 downregulation. Fmn2 deletion enhances microtubule dynamics, axon regeneration, and function recovery. Using gene signature of Fmn2 deletion identifies FDA-approved metaxalone recapitulating growth-promoting effects of Fmn2 deletion for PNI. [ABSTRACT FROM AUTHOR]