Degeneration of injured axons and dendrites requires restraint of a protective JNK signaling pathway by the transmembrane protein Raw.

The degeneration of injured axons involves a self-destruction pathway whose components and mechanism are not fully understood. Here we report a new regulator of axonal resilience. The transmembrane protein Raw is cell autonomously required for the degeneration of injured axons, dendrites and synapses in Drosophila melanogaster. In both male and female raw hypomorphic mutant or knockdown larvae, the degeneration of injured axons, dendrites and synapses from motoneurons and sensory neurons is strongly inhibited. This protection is insensitive to reduction in the levels of the NAD+ synthesis enzyme Nmnat (nicotinamide mononucleotide adenylyl transferase), but requires the JNK MAP Kinase and —transcription factors Fos and Jun (AP-1). While these factors are previously known to function in axonal injury signaling and regeneration, Raw9s function can be genetically separated from other axonal injury responses: Raw does not modulate JNK-dependent axonal injury signaling and regenerative responses, but instead restrains a protective pathway that inhibits the degeneration of axons, dendrites and synapses. While protection in raw mutants requires JNK, Fos and Jun, JNK also promotes axonal degeneration. These findings suggest the existence of multiple independent pathways that share modulation by JNK, Fos and Jun that influence how axons respond to stress and injury. SIGNIFICANCE STATEMENT Axonal degeneration is a major feature of neuropathies and nerve injuries, and occurs via a cell autonomous self-destruction pathway whose mechanism is poorly understood. This study reports the identification of a new regulator of axonal degeneration: the transmembrane protein Raw. Raw regulates a cell autonomous nuclear signaling pathway whose yet unknown downstream effectors protect injured axons, dendrites and synapses from degenerating. These findings imply that the susceptibility of axons to degeneration is strongly regulated in neurons. Future understanding the cellular pathway regulated by Raw, which engages the JNK MAP Kinase and Fos and Jun transcription factors, may suggest new strategies to increase the resiliency of axons in debilitating neuropathies.