BMP signaling downstream of the Highwire E3 ligase sensitizes nociceptors

PLoS Genetics
Ken Honjo, W Daniel Tracey

Abstract

A comprehensive understanding of the molecular machinery important for nociception is essential to improving the treatment of pain. Here, we show that the BMP signaling pathway regulates nociception downstream of the E3 ubiquitin ligase highwire (hiw). hiw loss of function in nociceptors caused antagonistic and pleiotropic phenotypes with simultaneous insensitivity to noxious heat but sensitized responses to optogenetic activation of nociceptors. Thus, hiw functions to both positively and negatively regulate nociceptors. We find that a sensory reception-independent sensitization pathway was associated with BMP signaling. BMP signaling in nociceptors was up-regulated in hiw mutants, and nociceptor-specific expression of hiw rescued all nociception phenotypes including the increased BMP signaling. Blocking the transcriptional output of the BMP pathway with dominant negative Mad suppressed nociceptive hypersensitivity that was induced by interfering with hiw. The up-regulated BMP signaling phenotype in hiw genetic mutants could not be suppressed by mutation in wallenda suggesting that hiw regulates BMP in nociceptors via a wallenda independent pathway. In a newly established Ca2+ imaging preparation, we observed that up-regulated ...Continue Reading

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Citations

Jun 20, 2019·Proceedings of the National Academy of Sciences of the United States of America·Jeffrey S DasonMarla B Sokolowski
Mar 7, 2020·Current Biology : CB·Prabhjit Singh, Jeffrey M Donlea
Jun 15, 2021·Frontiers in Molecular Neuroscience·Jiurong ChengJun Zhou

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Methods Mentioned

BETA
antisense oligonucleotide
dissection

Software Mentioned

Mathworks
NI Signal Express
Adobe Illustrator
Excel
Matlab

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