KIF4A: unravelling a potential spinal cord repair gene using regenerative peripheral nerve injury models

Abstract

Spinal cord injury (SCI) seriously impairs functions below injury level and has no effective treatment yet. Central neurons may be stimulated to regenerate in more permissive environments. Our mining for transcriptomic data from manipulated rodent SCI models presenting improved motor functions, retrieved sets of common differentially expressed genes (DEGs) involved in recovery. Amongst the up-regulated DEGs was KIF4A, an anterograde kinesin essential throughout development but downregulated postnatally. KIF4A is unaltered in the spinal cord of untreated SCI animals at the acute phase. This work aimed to characterize KIF4A levels and distribution in various PNS injury (PNI) regenerative rodent models. KIF4A signal was analysed by IHC(F) and qRT-PCR, in DRGs and distal nerve stumps, upon two PNI lesions (sciatic crush versus the less regenerative transection). KIF4A distribution was also studied in spinal cord tissues upon sciatic nerve transection. qRT-PCR revealed that KIF4A expression in sciatic nerve and DRGs is upregulated upon both lesion paradigms (2dpi). At 7dpi, KIF4A levels at the distal stump increase more than 15x. In both DRGs and distal stumps, KIF4A is particularly upregulated in the spontaneously regenerative crush paradigm. IHC(F) revealed basal KIF4A distribution in axons, DRGs neurons’ nuclei and Schwann cells. Following sciatic transection, KIF4A was observed in motor neurons’ nuclei at the spinal cord region to where injured sciatic nerve projects. Transcriptomic data mining and experimental data relate KIF4A levels with neuronal regeneration, where nuclear KIF4A may have anti-apoptotic roles. Subsequent functional assays must be addressed following modulation of KIF4A levels.