Netrin-3 Suppresses Diabetic Neuropathic Pain By Gating Axon Intra-epidermal Sprouting

Diabetic neuropathic pain(DNP)is a common symptom of diabetic polyneuropathy,clinically difficult to treat due to its elusive mechanism.Emerging evidence has linked DNP pathogenesis to the aberrant sprouting of sensory axons into the epidermal area;however,the underlying molecular events remain poorly understood.Here we found that an axon guidance molecule,Netrin-3(Ntn-3),was expressed in the sensory neurons of adult mouse and human dorsal root ganglions(DRGs),suggesting that it is involved in sensory function.In the STZ induced diabetes mouse model,we found that downregulation of Ntn-3 expression was highly correlated to the severity of DNP.Genetic ablation of Ntn-3 increased the intra-epidermal sprouting of sensory axons and worsened the DNP in diabetic mice.In contrast,the elevation of Ntn-3 levels in DRGs significantly inhibited the intra-epidermal axon sprouting and alleviated DNP in diabetic mice.Consistent with the observations in vivo in DN pathological conditions,Ntn-3 depletion was also found required for aggressive axonal outgrowth in primary cultured DN DRG neurons.Above all,our studies identified Ntn-3 as a vital regulator of DNP pathogenesis by gating the aberrant sprouting of sensory axons,indicating Ntn-3 could be a potential druggable target for DNP treatment.