Gene-teratogen interactions influence the penetrance of birth defects by altering Hedgehog signaling strength

Area of Science:

• Developmental biology
• Genetics
• Pharmacology

Background:

• Birth defects arise from complex genetic and environmental interactions, with underlying molecular mechanisms often unclear.
• Hedgehog (Hh) signaling is crucial for embryonic development, and its dysregulation can lead to congenital abnormalities.

Purpose of the Study:

• To elucidate the molecular mechanisms by which genetic mutations and teratogens interact to cause birth defects.
• To identify key protein complexes and signaling pathways involved in these interactions.

Main Methods:

• Investigated the role of the MOSMO component within the MMM complex in regulating Smoothened (SMO) stability.
• Utilized mouse models (Mosmo-/- embryos) and in utero exposure to teratogens targeting SMO.
• Analyzed changes in Hh signaling pathway activity and their correlation with birth defect phenotypes.

Main Results:

• Mutations and teratogens interact by modulating target cell sensitivity to Hedgehog (Hh) ligands.
• The MMM complex, particularly MOSMO, regulates SMO degradation, influencing Hh pathway activity.
• Loss of MOSMO leads to elevated SMO and increased Hh signaling, causing multiple birth defects.
• Teratogen-induced SMO inhibition reduced birth defect severity in Mosmo-/- embryos, demonstrating a quantitative relationship.

Conclusions:

• Genetic and environmental factors converge on the MMM complex to control Hh signaling, impacting birth defect development.
• The sensitivity of developmental processes to teratogens can be modulated by the genetic background and the abundance of the teratogen's target.
• Therapeutic strategies targeting Hh signaling strength show potential for rescuing structural birth defects.