Varicose and cheerio collaborate with pebble to mediate semaphorin-1a reverse signaling in Drosophila

Sangyun Jeong, Da som Yang, Young Gi Hong, Sarah P. Mitchell, Matthew P. Brown, Alex L. Kolodkin

Research output: Contribution to journalArticlepeer-review

Abstract

The transmembrane semaphorin Sema-1a acts as both a ligand and a receptor to regulate axon–axon repulsion during neural development. Pebble (Pbl), a Rho guanine nucleotide exchange factor, mediates Sema-1a reverse signaling through association with the N-terminal region of the Sema-1a intracellular domain (ICD), resulting in cytoskeletal reorganization. Here, we uncover two additional Sema-1a interacting proteins, varicose (Vari) and cheerio (Cher), each with neuronal functions required for motor axon pathfinding. Vari is a member of the membrane-associated guanylate kinase (MAGUK) family of proteins, members of which can serve as scaffolds to organize signaling complexes. Cher is related to actin filament cross-linking proteins that regulate actin cytoskeleton dynamics. The PDZ domain binding motif found in the most C-terminal region of the Sema-1a ICD is necessary for interaction with Vari, but not Cher, indicative of distinct binding modalities. Pbl/Sema-1a–mediated repulsive guidance is potenti-ated by both vari and cher. Genetic analyses further suggest that scaffolding functions of Vari and Cher play an important role in Pbl-mediated Sema-1a reverse signaling. These results define intracellular components critical for signal transduction from the Sema-1a receptor to the cytoskeleton and provide insight into mechanisms underlying semaphorin-induced localized changes in cytoskeletal organization.

Original languageEnglish (US)
Pages (from-to)E8254-E8263
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number39
DOIs
StatePublished - Sep 26 2017

Keywords

  • Cheerio
  • Pebble
  • Reverse signaling
  • Semaphorin-1a
  • Varicose

ASJC Scopus subject areas

  • General

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