UC San Diego

Following spinal cord injury (SCI), axons from the central nervous system (CNS) lack the ability to spontaneously repair and consequently the severed neuronal connections can result in physiological impairments. In order to develop effective treatments to mitigate these injury ailments, understanding the molecular mechanisms involved in axonal repair is of the utmost importance. While previous studies have made substantial progress expanding our knowledge about the extrinsic and neuron intrinsic pathways involved in CNS axonal repair, only a small percentage of neurons are capable of regenerating with molecular interventions. Investigating the regenerative heterogeneity of neurons post-injury might provide greater insight into the intrinsic mechanisms regulating axon growth. A recent study in our lab interrogated the molecular heterogeneity of non-regenerating and regenerating corticospinal (CST) neurons following SCI injury with patch-based single-cell RNA sequencing (scRNA-seq). The scRNA-seq data was analyzed and identified two genes as potential regulators of pathways contributing to axon regeneration: Nuclear Factor Erythroid-Derived 2-Like 2 (NFE2L2) and Peroxisome Proliferator-Activated Receptor Gamma, Coactivator-1-Alpha (PPARGC1A). We examined if NFE2L2 and PPARGC1A expression is required for CST axon growth in mouse CNS injury models. We observed deletion of NFE2L2 abolishes PTEN-induced axon regeneration and shows a trend of no negative effect upon PTEN-induced axon sprouting. As for the PPARGC1A regeneration study, the data remains inconclusive and awaits replicate studies to examine its role in axon growth. Our data highlights how NFE2L2 expression involved in antioxidant response can contribute to mechanisms tied with axon growth.