The Drosophila chromodomain protein Kismet activates steroid hormone receptor transcription to govern axon pruning and memory in vivo.
Axon pruning is critical for the proper synapse elimination required for sculpting precise neural circuits. Though axon pruning has been described in the literature for decades, relatively little is known about the molecular and cellular mechanisms that govern axon pruning in vivo. Here, we show that the epigenetic reader Kismet (Kis) binds to cisregulatory elements of the steroid hormone receptor Ecdysone Receptor (EcR) gene in Drosophila neurons. Kis is required to activate EcR transcription at these elements and promote H3K36 di- and tri-methylation and H4K16 acetylation. We show that exogenous EcR can rescue axon pruning and memory defects associated with loss of Kis, and that the histone deacetylase inhibitor SAHA can rescue these phenotypes. EcR protein abundance is a cell-autonomous, rate-limiting step required to initiate axon pruning in Drosophila, and our data suggests that this step is under epigenetic control.\n\nHighlights (bullet points up to 4)O_LIThe chromodomain reader Kismet activates transcription of the steroid hormone receptor EcR-B1 in the Drosophila to initiate developmental axon pruning.\nC_LIO_LIKismet promotes H3K36 di- and tri-methylation and H4K16 acetylation at the EcR locus and upstream cis-regulatory sites.\nC_LIO_LIAxon pruning and memory defects associated with loss of Kismet are significantly rescued by general HDAC inhibition.\nC_LI