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

Kellianne D. Alexander, Shankar Ramachandran, Kasturi Biswas, Christopher M. Lambert, Julia Russell, Devyn B. Oliver, William Armstrong, Monika Rettler, Samuel Liu, Maria Doitsidou, Claire Bénard, Amy K. Walker and Michael M. Francis ()
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Kellianne D. Alexander: University of Massachusetts Chan Medical School
Shankar Ramachandran: University of Massachusetts Chan Medical School
Kasturi Biswas: University of Massachusetts Chan Medical School
Christopher M. Lambert: University of Massachusetts Chan Medical School
Julia Russell: University of Massachusetts Chan Medical School
Devyn B. Oliver: University of Massachusetts Chan Medical School
William Armstrong: University of Massachusetts Chan Medical School
Monika Rettler: University of Massachusetts Chan Medical School
Samuel Liu: University of Massachusetts Chan Medical School
Maria Doitsidou: University of Edinburgh
Claire Bénard: University of Massachusetts Chan Medical School
Amy K. Walker: University of Massachusetts Chan Medical School
Michael M. Francis: University of Massachusetts Chan Medical School

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract The elimination of synapses during circuit remodeling is critical for brain maturation; however, the molecular mechanisms directing synapse elimination and its timing remain elusive. We show that the transcriptional regulator DVE-1, which shares homology with special AT-rich sequence-binding (SATB) family members previously implicated in human neurodevelopmental disorders, directs the elimination of juvenile synaptic inputs onto remodeling C. elegans GABAergic neurons. Juvenile acetylcholine receptor clusters and apposing presynaptic sites are eliminated during the maturation of wild-type GABAergic neurons but persist into adulthood in dve-1 mutants, producing heightened motor connectivity. DVE-1 localization to GABAergic nuclei is required for synapse elimination, consistent with DVE-1 regulation of transcription. Pathway analysis of putative DVE-1 target genes, proteasome inhibitor, and genetic experiments implicate the ubiquitin-proteasome system in synapse elimination. Together, our findings define a previously unappreciated role for a SATB family member in directing synapse elimination during circuit remodeling, likely through transcriptional regulation of protein degradation processes.

Date: 2023
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DOI: 10.1038/s41467-023-43281-4

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