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Updated: May 27, 2025

Quantitative PCR-based Assay to Measure Sonic Hedgehog Signaling in Cellular Model of Ciliogenesis
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Receptor Allostery Promotes Context-Dependent Sonic Hedgehog Signaling During Embryonic Development.

Shariq S Ansari1, Miriam E Dillard1, Mohamed Ghonim2

  • 1Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.

Biorxiv : the Preprint Server for Biology
|February 20, 2025
PubMed
Summary
This summary is machine-generated.

Arachidonic acid (AA) binding to Smoothened (SMO) is crucial for Sonic Hedgehog (SHH) pathway activity during embryonic development. Disrupting this binding causes severe heart and lung defects in mice.

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Area of Science:

  • Developmental Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Sonic Hedgehog (SHH) signaling is essential for embryonic development, patterning diverse tissues.
  • The signal transducer Smoothened (SMO) is activated by ligands including sterols, oxysterols, and arachidonic acid (AA).
  • Allosteric regulation of SMO by combinatorial ligand binding is suggested by in vitro studies, but in vivo evidence is lacking.

Purpose of the Study:

  • To investigate the in vivo role of arachidonic acid (AA) binding in Smoothened (SMO) allosteric regulation.
  • To elucidate the functional consequences of disrupted AA binding to SMO during embryogenesis.
  • To determine the impact of compromised SMO-AA interaction on SHH pathway activity and tissue development.

Main Methods:

  • Mapping of an AA binding pocket within the 7-transmembrane (7TM) bundle of SMO.
  • Generation and analysis of a knockin mouse model with compromised AA binding to SMO.
  • Assessment of SHH pathway induction and developmental phenotypes in mutant mice.

Main Results:

  • Disruption of the AA binding pocket attenuates SHH and sterol-stimulated SMO induction.
  • Homozygous mutant mice exhibit cyanosis, high perinatal lethality, and congenital heart disease.
  • Surviving mutants display pulmonary maldevelopment and failure to thrive, while neurodevelopment remains unaffected.

Conclusions:

  • Arachidonic acid (AA) binding to SMO is critical for SHH pathway activation in vivo.
  • Context-dependent allosteric regulation of SMO by AA is essential for proper cardiopulmonary development.
  • Compromised SMO-AA interaction leads to severe developmental defects, highlighting the pathway's role in heart and lung formation.