The homeodomain transcriptional regulator DVE-1 directs a program for synapse elimination during circuit remodeling

Abstract

An important step in brain development is the remodeling of juvenile neural circuits to establish mature connectivity. The elimination of juvenile synapses is a critical step in this process; however, the molecular mechanisms directing synapse elimination processes and their timing are not fully understood. We identify here a conserved transcriptional regulator, DVE-1, that directs the elimination of juvenile synaptic inputs onto remodelingC. elegansGABAergic neurons. Dorsally localized juvenile acetylcholine receptor clusters and apposing presynaptic sites are eliminated during maturation of wild type GABAergic neurons but persist into adulthood indve-1mutants. The persistence of juvenile synapses indve-1mutants does not impede synaptic growth during GABAergic remodeling and therefore results in heightened motor connectivity, producing a turning bias during movement. DVE-1 is localized to GABAergic nuclei prior to remodeling and DVE-1 nuclear localization is required for synapse elimination to proceed. Synaptic remodeling is antagonized by the expression of the Ig domain protein OIG-1. Premature synapse elimination inoig-1mutants is reversed bydve-1mutation, while precocious synaptic growth is unaffected, indicating a functional separation of synapse destruction and growth during remodeling. Together, our findings demonstrate a novel strategy for sculpting mature connectivity through the coordination of parallel DVE-1-regulated pro-degenerative processes and temporally regulated maintenance mechanisms.Contributions SummaryK.D.A. generated strains, transgenic lines, molecular constructs, confocal microscopy images and analysis, performed optogenetic behavioral experiments, photoconversion experiments, modencode ChIP-seq analysis and pathway analysis. S.R, performed all calcium imaging experiments/analysis and conducted single worm tracking. C.L. generated most vectors and constructs. J.R. assisted with generation of CRISPR/Cas9 generated strains. W.A. and M.R. assisted with aldicarb behavioral assay. D.O. assisted with EMS screen and isolation ofdve-1mutant. C.B. and M. D. aided in CloudMap bioinformatic analysis of uf171 mutant. M.M.F. and K.D.A designed and interpreted results of all experiments and wrote the manuscript.