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Receptor Allostery Promotes Sonic Hedgehog Signaling During Embryonic Development

GSE283994 Mus musculus Expression profiling by high throughput sequencing 8 samples Submitted 2025/02/26 Platform GPL24247
Summary
Sonic Hedgehog (SHH) signaling functions in temporal and context-dependent manners to pattern diverse tissues during embryogenesis. The signal transducer Smoothened (SMO) is regulated 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 the CRD and 7TM pockets but in vivo evidence of SMO allostery is lacking. Herein, we demonstrate that disruption of AA binding to a pocket at the top of the 7TM attenuates SHH and sterol-stimulated SMO activity. We generated a knockin mouse model of compromised AA binding and show that homozygous mutants are cyanotic with high perinatal lethality. Surviving animals fail to thrive due to cardiopulmonary mispatterning. Neurodevelopment is unaltered in these mice, suggesting context-dependent allosteric regulation of SMO signaling allows for precise tuning of pathway activity for heart and lung development.
Published in
Receptor Allostery Promotes Context-Dependent Sonic Hedgehog Signaling During Embryonic Development
Ansari SS, Dillard ME, Ghonim M et al. · bioRxiv : the preprint server for biology 2025 · PMID 39975106 · doi:10.1101/2025.01.28.635336
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Also filed as BioProject PRJNA1196536 and SRA study SRP550644. Searching any of these in the dataset finder brings you back here.

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