ArticleDevelopment (Cambridge, England)2021
Gene-teratogen interactions influence the penetrance of birth defects by altering Hedgehog signaling strength.
Article in Development (Cambridge, England), 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 12 citations in OpenAlex.
- Convergent mechanisms in Wnt and Hedgehog signaling.Science signaling · 2026Review
- Article
- Design principles of a membrane-spanning ubiquitin ligase.Molecular cell · 2026Article
- MGRN1 in development and disease: a unifying view of a versatile membrane-tethered E3 ubiquitin ligase.Biochemical Society transactions · 2026Review
- Functional impact of genetic background on variable expressivity in neurodevelopmental disorders.Nature communications · 2026Article
- The E3 ubiquitin ligase MGRN1 targets melanocortin receptors MC1R and MC4R via interactions with transmembrane adapters.Journal of cell science · 2025Article
- Loss-of-function variants in ciliary genes confer high risk for tetralogy of Fallot.Science advances · 2025Article
- "Design principles of a membrane-spanning ubiquitin ligase".bioRxiv : the preprint server for biology · 2025Article
- An integrated framework for functional dissection of variable expressivity in genetic disorders.medRxiv : the preprint server for health sciences · 2025Article
- Exploring pathogenesis, prevalence, and genetic associations in Chiari malformation type 1: a contemporary perspective.Asian biomedicine : research, reviews and news · 2024Review
- Receptor control by membrane-tethered ubiquitin ligases in development and tissue homeostasis.Current topics in developmental biology · 2022Article
- Analysis of Gene-Environment Interactions Related to Developmental Disorders.Frontiers in pharmacology · 2022Review
- Mosmo Is Required for Zebrafish Craniofacial Formation.Frontiers in cell and developmental biology · 2021Article
- Article
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Authors and funding
14 authors at 4 institutions in 1 country.
Funding
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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