{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T01:53:19Z","timestamp":1781229199593,"version":"3.54.1"},"reference-count":25,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2017,1,23]],"date-time":"2017-01-23T00:00:00Z","timestamp":1485129600000},"content-version":"vor","delay-in-days":3,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U54AA019756"],"award-info":[{"award-number":["U54AA019756"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["K99\/R00\u2010AA018697"],"award-info":[{"award-number":["K99\/R00\u2010AA018697"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U01\u2010AA0216521"],"award-info":[{"award-number":["U01\u2010AA0216521"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Birth Defects Research"],"published-print":{"date-parts":[[2017,1,20]]},"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>While pharmacological activation of the Hedgehog (HH) signaling pathway may have therapeutic benefits for developmental and adult diseases, its teratogenic potential is of concern. The membrane molecule Smoothened (SMO) transduces HH signaling and can be acutely modulated by antagonists and agonists. The objective of the current experiments was to determine how maternal treatment with the Smo agonist, SAG, affects the developing limb.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Pregnant C57BL\/6J mice received a single injection of SAG (15, 17, or 20 mg\/kg, i.p.) or its vehicle on gestational day (GD) 9.25, the time of limb bud induction. Embryos were examined on GD 15 for gross dysmorphology and skeletal staining was performed to visualize the number and type of digits on the fore\u2010 and hindlimbs. Additionally, in situ hybridization was performed 4 hr after GD 9.25 SAG administration to determine SAG's effects on <jats:italic>Gli1<\/jats:italic> and <jats:italic>Gli2<\/jats:italic> mRNA expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The most prevalent effect of SAG was the dose\u2010dependent induction of pre\u2010axial polydactyly; defects ranged from a broad thumb to the duplication of two finger\u2010like digits on the preaxial side of the thumb. The highest SAG dose was effective in ca. 80% of the embryos and increased <jats:italic>Gli1<\/jats:italic> and <jats:italic>Gli2<\/jats:italic> mRNA expression in the limb bud, with <jats:italic>Gli1<\/jats:italic> mRNA being the most upregulated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Preaxial polydactyly can be caused in the developing embryo by acute maternal administration of a Smo agonist that activates HH signaling. These results are consistent with the preaxial polydactyly induced in developmental disorders associated with mutations in HH signaling genes.Birth Defects Research 109:49\u201354, 2017. \u00a9 2016 Wiley Periodicals, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/bdra.23571","type":"journal-article","created":{"date-parts":[[2016,11,1]],"date-time":"2016-11-01T14:39:30Z","timestamp":1478011170000},"page":"49-54","source":"Crossref","is-referenced-by-count":14,"title":["Preaxial polydactyly following early gestational exposure to the smoothened agonist, SAG, in C57BL\/6J mice"],"prefix":"10.1002","volume":"109","author":[{"given":"Eric W.","family":"Fish","sequence":"first","affiliation":[{"name":"Bowles Center for Alcohol Studies University of North Carolina Chapel Hill North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott E.","family":"Parnell","sequence":"additional","affiliation":[{"name":"Bowles Center for Alcohol Studies University of North Carolina Chapel Hill North Carolina"},{"name":"Department of Cell Biology and Physiology University of North Carolina Chapel Hill North Carolina"},{"name":"Carolina Institute for Developmental Disabilities University of North Carolina Chapel Hill North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen K.","family":"Sulik","sequence":"additional","affiliation":[{"name":"Bowles Center for Alcohol Studies University of North Carolina Chapel Hill North Carolina"},{"name":"Department of Cell Biology and Physiology University of North Carolina Chapel Hill North Carolina"},{"name":"Carolina Institute for Developmental Disabilities University of North Carolina Chapel Hill North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorinda K.","family":"Baker","sequence":"additional","affiliation":[{"name":"Bowles Center for Alcohol Studies University of North Carolina Chapel Hill North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura B.","family":"Murdaugh","sequence":"additional","affiliation":[{"name":"Bowles Center for Alcohol Studies University of North Carolina Chapel Hill North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Lamson","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, BRITE Institute North Carolina Central University Durham North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin P.","family":"Williams","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, BRITE Institute North Carolina Central University Durham North 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