Gene-teratogen interactions influence the penetrance of birth defects by altering Hedgehog signaling strength.
Development
; 148(19)2021 10 01.
Article
em En
| MEDLINE
| ID: mdl-34486668
ABSTRACT
Birth defects result from interactions between genetic and environmental factors, but the mechanisms remain poorly understood. We find that mutations and teratogens interact in predictable ways to cause birth defects by changing target cell sensitivity to Hedgehog (Hh) ligands. These interactions converge on a membrane protein complex, the MMM complex, that promotes degradation of the Hh transducer Smoothened (SMO). Deficiency of the MMM component MOSMO results in elevated SMO and increased Hh signaling, causing multiple birth defects. In utero exposure to a teratogen that directly inhibits SMO reduces the penetrance and expressivity of birth defects in Mosmo-/- embryos. Additionally, tissues that develop normally in Mosmo-/- embryos are refractory to the teratogen. Thus, changes in the abundance of the protein target of a teratogen can change birth defect outcomes by quantitative shifts in Hh signaling. Consequently, small molecules that re-calibrate signaling strength could be harnessed to rescue structural birth defects.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Anormalidades Induzidas por Medicamentos
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Penetrância
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Proteínas Hedgehog
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Interação Gene-Ambiente
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article