{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T17:52:57Z","timestamp":1791049977575,"version":"4.1.0"},"reference-count":38,"publisher":"The Company of Biologists","issue":"20","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2010,10,15]]},"abstract":"<jats:p>Variation is an intrinsic feature of biological systems, yet developmental biology does not frequently address population-level phenomena. Sonic hedgehog (SHH) signaling activity in the vertebrate forebrain and face is thought to contribute to continuous variation in the morphology of the upper jaw, but despite its potential explanatory power, this idea has never been quantitatively assessed. Here, we test this hypothesis with an experimental design that is explicitly focused on the generation and measurement of variation in multivariate shape, tissue growth, cellular behavior and gene expression. We show that the majority of upper jaw shape variation can be explained by progressive changes in the spatial organization and mitotic activity of midfacial growth zones controlled by SHH signaling. In addition, nonlinearity between our treatment doses and phenotypic outcomes suggests that threshold effects in SHH signaling may play a role in variability in midfacial malformations such as holoprosencephaly (HPE). Together, these results provide novel insight into the generation of facial morphology, and demonstrate the value of quantifying variation for our understanding of development and disease.<\/jats:p>","DOI":"10.1242\/dev.052340","type":"journal-article","created":{"date-parts":[[2010,9,8]],"date-time":"2010-09-08T20:59:21Z","timestamp":1283979561000},"page":"3405-3409","source":"Crossref","is-referenced-by-count":137,"title":["Quantitative analyses link modulation of sonic hedgehog signaling to continuous variation in facial growth and shape"],"prefix":"10.1242","volume":"137","author":[{"given":"Nathan M.","family":"Young","sequence":"first","affiliation":[{"name":"University of California, San Francisco, Department of Orthopaedic Surgery, Building 9, Room 342, 2550 23rd Street, San Francisco, CA 94110, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. Jonathan","family":"Chong","sequence":"additional","affiliation":[{"name":"University of California, San Francisco, School of Medicine, San Francisco, CA 94143, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane","family":"Hu","sequence":"additional","affiliation":[{"name":"University of California, San Francisco, Department of Orthopaedic Surgery, Building 9, Room 342, 2550 23rd Street, San Francisco, CA 94110, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benedikt","family":"Hallgr\u00edmsson","sequence":"additional","affiliation":[{"name":"University of Calgary, Department of Cell Biology and Anatomy, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralph S.","family":"Marcucio","sequence":"additional","affiliation":[{"name":"University of California, San Francisco, Department of Orthopaedic Surgery, Building 9, Room 342, 2550 23rd Street, San Francisco, CA 94110, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042606004934500_R1","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.1101\/gad.1543607","article-title":"The Hedgehog-binding proteins Gas1 and Cdo cooperate to positively regulate Shh signaling during mouse development","volume":"21","author":"Allen","year":"2007","journal-title":"Genes Dev."},{"key":"2021042606004934500_R2","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1002\/ajmg.a.32167","article-title":"The clinical atlas of Greig cephalopolysyndactyly syndrome","volume":"146A","author":"Balk","year":"2008","journal-title":"Am. 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