Transcription factor Pebbled/RREB1 regulates injury-induced axon degeneration.

Abstract

Genetic studies of Wallerian degeneration have led to the identification of signaling molecules (e.g., dSarm/Sarm1, Axundead, and Highwire) that function locally in axons to drive degeneration. Here we identify a role for the <i>Drosophila</i> C₂H₂ zinc finger transcription factor Pebbled [Peb, Ras-responsive element binding protein 1 (RREB1) in mammals] in axon death. Loss of Peb in <i>Drosophila</i> glutamatergic sensory neurons results in either complete preservation of severed axons, or an axon death phenotype where axons fragment into large, continuous segments, rather than completely disintegrate. Peb is expressed in developing and mature sensory neurons, suggesting it is required to establish or maintain their competence to undergo axon death. <i>peb</i> mutant phenotypes can be rescued by human RREB1, and they exhibit dominant genetic interactions with <i>dsarm</i> mutants, linking <i>peb/RREB1</i> to the axon death signaling cascade. Surprisingly, Peb is only able to fully block axon death signaling in glutamatergic, but not cholinergic sensory neurons, arguing for genetic diversity in axon death signaling programs in different neuronal subtypes. Our findings identify a transcription factor that regulates axon death signaling, and <i>peb</i> mutant phenotypes of partial fragmentation reveal a genetically accessible step in axon death signaling.