Transcriptional profiling of the injured sciatic nerve of mice carrying the Wld(S) mutant gene: Identification of genes involved in neuroprotection, neuroinflammation, and nerve regeneration

Authors

Benoit Barrette, Ezéquiel Calvo, Nicolas Vallières and Steve Lacroix

Abstract

Wallerian degeneration (WD) involves the fragmentation of axonal segments disconnected from their cell bodies, segmentation of the myelin sheath, and removal of debris by Schwann cells and immune cells. The removal and downregulation of myelin-associated inhibitors of axonal regeneration and synthesis of growth factors by these two cell types are critical responses to successful nerve repair. Here, we analyzed the transcriptome of the sciatic nerve of mice carrying the Wallerian degeneration slow (WldS) mutant gene, a gene that confers axonal protection in the distal stump after injury, therefore causing significant delays in WD, neuroinflammation, and axonal regeneration. Of the thousands of genes analyzed by microarray, 719 transcripts were differentially expressed between WldS and wild-type (wt) mice. Notably, the Nmnat1, a transcript contained within the sequence of the WldS gene, was upregulated by five to eightfold in the sciatic nerve of naive WldS mice compared with wt. The injured sciatic nerve of wt could be further distinguished from the one of WldS mice by the preferential upregulation of genes involved in axonal processes and plasticity (Chl1, Epha5, Gadd45b, Jun, Nav2, Nptx1, Nrcam, Ntm, Sema4f), inflammation and immunity (Arg1, Lgals3, Megf10, Panx1), growth factors/cytokines and their receptors (Clcf1, Fgf5, Gdnf, Gfrα1, Il7r, Lif, Ngfr/p75NTR, Shh), and cell adhesion and extracellular matrix (Adam8, Gpc1, Mmp9, Tnc). These results will help understand how the nervous and immune systems interact to modulate nerve repair, and identify the molecules that drive these responses. Gene profiling of the sciatic nerve of Wallerian degeneration slow (WldS) mutant mice. The WldS mutation causes delays in neuroinflammation and axonal regeneration. Genes that promote axon growth (Chl1, Clcf1, Fgf5, Gdnf, Jun, Lif, Nav2, Nrcam, Ntm, Shh) are downregulated in WldS mice. Injured WldS mice express more strongly axon growth inhibitory molecules found in myelin and scar tissue. Genes associated with immunosuppression (e.g. Fpr2, Cd55, Cd59) are expressed at higher levels in mutants. IFN-α/ß signaling pathway could also contribute to immunosuppression in WldS mutants.