UC San Diego

The identification of cell intrinsic factors that enhance the regeneration of central nervous system (CNS) axons is of particular interest for axon growth and functional recovery following traumatic injury to the nervous system. We have taken both an unbiased and hypothesis-driven approach to identify candidate factors that have the potential to enhance the regenerative capacity of injured CNS neurons. Candidates identified by both approaches were analyzed using in vitro and in vivo models to assess their potential in promoting growth of injured axons. In the unbiased approach, multiple datasets derived from whole genome transcriptional profiling of regenerating dorsal root ganglion (DRGs) cells were used to identify a sub-set of transcription factors predicted to be master regulators of regeneration. These candidates were tested for their regenerative potential in vitro in DRGs utilizing lentiviral gene transfer. Using a hypothesis-driven approach, we selected candidate factors based on a known role in axon establishment and growth during development. In this study, we identify a novel role for protein kinase M zeta (PKM-[zeta]) and atypical protein kinase C iota/ lambda (aPKC-[lambda]). These were recently shown to regulate axon specification in developing CNS neurons. Our results suggest that PKM-[zeta] acts as a negative regulator and aPKC-[lambda] functions as a positive regulator of neurite outgrowth in adult DRGs. Complementary in vivo experiments in axon regeneration after optic nerve and dorsal column injury reveal inconclusive data in regards to the role of PKM-[zeta] and aPKC-[lambda] in axon regeneration