Shep regulates neuronal remodeling by controlling transcription of its chromatin targets.

Neuronal remodeling is crucial for formation of the mature nervous system and disruption of this process can lead to neuropsychiatric diseases. Global gene expression changes in neurons during remodeling as well as the factors that regulate these changes remain poorly defined. To elucidate this process, we performed RNA-seq on isolated larval and pupal neurons and found upregulated synaptic signaling and downregulated gene expression regulators as a result of normal neuronal metamorphosis. We further tested the role of (), which encodes an evolutionarily conserved RNA-binding protein required for proper neuronal remodeling. Depletion of in neurons prevents the execution of metamorphic gene expression patterns, and regulated genes correspond to Shep chromatin and/or RNA-binding targets. Reduced expression of a Shep-inhibited target gene that we identified, , is sufficient to rescue neuronal remodeling defects of knockdown flies. Our results reveal direct regulation of transcriptional programs by Shep to regulate neuronal remodeling during metamorphosis.