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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\u2212\/\u2212 embryos. Additionally, tissues that develop normally in Mosmo\u2212\/\u2212 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.<\/jats:p>","DOI":"10.1242\/dev.199867","type":"journal-article","created":{"date-parts":[[2021,9,6]],"date-time":"2021-09-06T14:11:41Z","timestamp":1630937501000},"source":"Crossref","is-referenced-by-count":17,"title":["Gene-teratogen interactions influence the penetrance of birth defects by altering Hedgehog signaling strength"],"prefix":"10.1242","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4573-3270","authenticated-orcid":false,"given":"Jennifer H.","family":"Kong","sequence":"first","affiliation":[{"name":"Departments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cullen B.","family":"Young","sequence":"additional","affiliation":[{"name":"Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1406-2566","authenticated-orcid":false,"given":"Ganesh V.","family":"Pusapati","sequence":"additional","affiliation":[{"name":"Departments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F. 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