Receptor allostery promotes context-specific Sonic Hedgehog signaling during embryonic development
Abstract Sonic Hedgehog (SHH) signaling functions in temporal- and context-dependent manners to pattern diverse tissues during embryogenesis. The signal transducer Smoothened (SMO) is induced by sterols, oxysterols, and arachidonic acid (AA) through binding pockets in its extracellular cysteine-rich domain (CRD) and 7-transmembrane (7TM) bundle. In vitro analyses suggest SMO signaling is allosterically enhanced by combinatorial ligand binding to these pockets, but in vivo evidence of SMO allostery is lacking. Herein, we map an AA binding pocket at the top of the 7TM bundle and show that its disruption attenuates SHH- and sterol-stimulated SMO induction. A knock-in mouse model of compromised AA binding reveals that homozygous mutant mice are cyanotic, exhibit perinatal lethality, and display congenital heart disease. Surviving mutants demonstrate pulmonary maldevelopment and fail to thrive. Neurodevelopment is unaltered in these mice, suggesting that context-specific allosteric regulation of SMO signaling allows for precise tuning of pathway activity during cardiopulmonary development.
Authors
- Miriam E. Dillard (ORCID: https://orcid.org/0000-0002-0719-275X)
- Taosheng Chen (ORCID: https://orcid.org/0000-0001-6420-3809)
- Paul Glyndwr Thomas (ORCID: https://orcid.org/0000-0001-7955-0256)
- April Sykes (ORCID: https://orcid.org/0000-0002-7667-8155)
- Shondra M. Pruett‐Miller (ORCID: https://orcid.org/0000-0002-3793-585X)
- Daniel P. Stewart (ORCID: https://orcid.org/0009-0001-3559-7332)
- Ivan P. Moskowitz (ORCID: https://orcid.org/0000-0003-0014-4963)
- Robin Canac (ORCID: https://orcid.org/0000-0002-9036-1496)
- Stacey K. Ogden (ORCID: https://orcid.org/0000-0001-8991-3065)
- Samantha J. Hack (ORCID: https://orcid.org/0000-0002-3638-4750)
- James P. Bridges (ORCID: https://orcid.org/0000-0002-4815-117X)
- Christina A. Daly (ORCID: https://orcid.org/0000-0001-7470-0454)
- Jeffrey Steinberg (ORCID: https://orcid.org/0000-0003-4110-3586)
- William C. Wright (ORCID: https://orcid.org/0000-0002-2274-9966)
- Motomi Mori (ORCID: https://orcid.org/0000-0003-1390-4917)
- Yong‐Dong Wang (ORCID: https://orcid.org/0000-0001-8751-9216)
- Rojalin Pradhan
- Christopher C. Hom
- Mohamed A. Ghonim
- Yan Zhang
- Shariq S. Ansari
Institutions
- St. Jude Children's Research Hospital (US)
- National Jewish Health (US)
- University of Chicago (US)
- University of Colorado Anschutz Medical Campus (US)
- University of Colorado Denver (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-07-24
- DOI
- https://doi.org/10.1038/s41467-026-75918-5
- Primary Topic
- Hedgehog Signaling Pathway Studies
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Cancer Institute
- National Institute of General Medical Sciences