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Getting Hedgehogs Where They Need to Go: Furin Cleavage Activates Dispatched for Sonic Hedgehog Transport
Author(s) -
Ogden Stacey
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.00059
Subject(s) - furin , sonic hedgehog , smoothened , hedgehog , hedgehog signaling pathway , morphogen , microbiology and biotechnology , patched , biology , transmembrane protein , morphogenesis , cleavage (geology) , cyclopamine , genetics , signal transduction , receptor , gene , biochemistry , paleontology , fracture (geology) , enzyme
Hedgehog ligands activate an evolutionarily conserved signaling pathway that provides instructional cues during tissue morphogenesis, and when corrupted, contributes to developmental disorders and cancer. The transmembrane protein Dispatched is an essential component of the machinery that deploys Hedgehog family ligands from producing cells, and is required for Hedgehog morphogen gradient formation and signaling to long‐range targets. Molecular mechanisms that regulate Dispatched to control Hedgehog release are not yet defined. We reveal that Dispatched is activated by Furin‐mediated cleavage at a conserved processing site in its first extracellular loop. Disruption of Furin cleavage alters Dispatched membrane trafficking and attenuates Sonic Hedgehog release from ligand‐producing cells. CRISPR/Cas9 gene editing was used to generate transgenic mice harboring a cleavage site mutation in the endogenous Dispatched locus. Homozygous animals show neuronal patterning phenotypes and decreased viability, confirming a requirement for Dispatched processing in vivo . As such, Furin serves as a crucial post‐translational regulator of Dispatched activity in Hedgehog‐producing cells during tissue morphogenesis.