A Systems-Level Analysis of the Peripheral Nerve Intrinsic Axonal Growth Program

• We identify a transcriptional program observed after PNS, but not CNS injury
• This program links known signaling pathways via a core set of transcription factors
• We experimentally and bio-informatically validate several network predictions
• We use the core transcriptional profile to identify a drug that promotes regeneration

SummaryThe regenerative capacity of the injured CNS in adult mammals is severely limited, yet axons in the peripheral nervous system (PNS) regrow, albeit to a limited extent, after injury. We reasoned that coordinate regulation of gene expression in injured neurons involving multiple pathways was central to PNS regenerative capacity. To provide a framework for revealing pathways involved in PNS axon regrowth after injury, we applied a comprehensive systems biology approach, starting with gene expression profiling of dorsal root ganglia (DRGs) combined with multi-level bioinformatic analyses and experimental validation of network predictions. We used this rubric to identify a drug that accelerates DRG neurite outgrowth in vitro and optic nerve outgrowth in vivo by inducing elements of the identified network. The work provides a functional genomics foundation for understanding neural repair and proof of the power of such approaches in tackling complex problems in nervous system biology.