AT-rich interaction domain 5A facilitates axon regeneration through docking protein 6 in the peripheral nervous...

Peripheral nerves are easily damaged in accidental trauma due to their shallow location. Compared to the limited regeneration of the central nerve, the peripheral nerve has a certain regenerative ability after injury. However, this ability is not sufficient to achieve functional recovery. To increase the rate of regeneration after nerve injury, increasing regeneration-associated gene expression by transcription factors in neurons is necessary.

Sciatic nerve crush animal models were generated in Sprague-Dawley rats. Bioinformatics analysis and quantitative real-time polymerase chain reaction were applied to detect gene expression; immunofluorescence staining and western blotting were applied to detect protein expression. The neurite outgrowth of cultured dorsal root ganglion (DRG) neurons was performed to evaluate axon regeneration in vitro. Intrathecal injection of adeno-associated virus was applied to suppress or overexpress the target in vivo. Following transfection, immunofluorescence staining of newborn axons' marker (SCG10) in sciatic nerve after crush was used to evaluate the function of AT-rich interaction domain 5A (Arid5a) or docking protein 6 (Dok6) on axon regeneration. The binding between transcription factor (TF) and the promoter of target genes was verified by chromatin immunoprecipitation.

Arid5a has high activity in specific regenerating clusters and it accumulates specifically in the nucleus of DRG neurons after sciatic nerve injury. Upon Arid5a inhibition by small interfering RNA, the outgrowth of neurites in vitro and the regeneration of axons in vivo were inhibited. In contrast, after Arid5a overexpression in rats, axon regeneration was significantly accelerated. In addition, Arid5a promotes the expression of Dok6 by binding to its promoter in DRG neurons. Suppression of Dok6 represses the neurites outgrowth of cultured DRG neurons, while its overexpression enhances axon regeneration in vivo. Furthermore, overexpression of Dok6 restored the impaired effect of Arid5a suppression on axon regeneration.

These findings indicate that axonal injury induced nucleus accumulation of Arid5a in neurons. Through Dok6, Arid5a accelerates axon regeneration of DRG neurons both in vitro and in vivo. This study enriched our understanding of the function of Arid5a in the peripheral nervous system and the transcriptional regulatory network involved in neural regeneration.