{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T08:44:16Z","timestamp":1790066656227,"version":"4.0.1"},"reference-count":49,"publisher":"The Company of Biologists","issue":"15","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2012,8,1]]},"abstract":"<jats:p>Lesions in the epithelially expressed human gene FRAS1 cause Fraser syndrome, a complex disease with variable symptoms, including facial deformities and conductive hearing loss. The developmental basis of facial defects in Fraser syndrome has not been elucidated. Here we show that zebrafish fras1 mutants exhibit defects in facial epithelia and facial skeleton. Specifically, fras1 mutants fail to generate a late-forming portion of pharyngeal pouch 1 (termed late-p1) and skeletal elements adjacent to late-p1 are disrupted. Transplantation studies indicate that fras1 acts in endoderm to ensure normal morphology of both skeleton and endoderm, consistent with well-established epithelial expression of fras1. Late-p1 formation is concurrent with facial skeletal morphogenesis, and some skeletal defects in fras1 mutants arise during late-p1 morphogenesis, indicating a temporal connection between late-p1 and skeletal morphogenesis. Furthermore, fras1 mutants often show prominent second arch skeletal fusions through space occupied by late-p1 in wild type. Whereas every fras1 mutant shows defects in late-p1 formation, skeletal defects are less penetrant and often vary in severity, even between the left and right sides of the same individual. We interpret the fluctuating asymmetry in fras1 mutant skeleton and the changes in fras1 mutant skeletal defects through time as indicators that skeletal formation is destabilized. We propose a model wherein fras1 prompts late-p1 formation and thereby stabilizes skeletal formation during zebrafish facial development. Similar mechanisms of stochastic developmental instability might also account for the high phenotypic variation observed in human FRAS1 patients.<\/jats:p>","DOI":"10.1242\/dev.074906","type":"journal-article","created":{"date-parts":[[2012,7,10]],"date-time":"2012-07-10T14:18:21Z","timestamp":1341929901000},"page":"2804-2813","source":"Crossref","is-referenced-by-count":32,"title":["<i>fras1<\/i>shapes endodermal pouch 1 and stabilizes zebrafish pharyngeal skeletal development"],"prefix":"10.1242","volume":"139","author":[{"given":"Jared Coffin","family":"Talbot","sequence":"first","affiliation":[{"name":"Institute of Neuroscience, 1254 University of Oregon, Eugene, OR 97403-1254, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Macie B.","family":"Walker","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Colorado Denver Anshutz Medical Campus, Aurora, Colorado 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas J.","family":"Carney","sequence":"additional","affiliation":[{"name":"Institute of Molecular and Cell Biology, Proteos, Singapore 138673"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyler R.","family":"Huycke","sequence":"additional","affiliation":[{"name":"Institute of Neuroscience, 1254 University of Oregon, Eugene, OR 97403-1254, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Lin","family":"Yan","sequence":"additional","affiliation":[{"name":"Institute of Neuroscience, 1254 University of Oregon, Eugene, OR 97403-1254, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth A.","family":"BreMiller","sequence":"additional","affiliation":[{"name":"Institute of Neuroscience, 1254 University of Oregon, Eugene, OR 97403-1254, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Gai","sequence":"additional","affiliation":[{"name":"Institute of Neuroscience, 1254 University of Oregon, Eugene, OR 97403-1254, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"April","family":"DeLaurier","sequence":"additional","affiliation":[{"name":"Institute of Neuroscience, 1254 University of Oregon, Eugene, OR 97403-1254, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John H.","family":"Postlethwait","sequence":"additional","affiliation":[{"name":"Institute of Neuroscience, 1254 University of Oregon, Eugene, OR 97403-1254, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Hammerschmidt","sequence":"additional","affiliation":[{"name":"Institute for Developmental Biology, Center for Molecular Medicine Cologne, and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50937 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles B.","family":"Kimmel","sequence":"additional","affiliation":[{"name":"Institute of Neuroscience, 1254 University of Oregon, Eugene, OR 97403-1254, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042606211857300_R1","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1016\/j.ajhg.2009.08.010","article-title":"FREM1 mutations cause bifid nose, renal agenesis, and anorectal malformations syndrome","volume":"85","author":"Alazami","year":"2009","journal-title":"Am. 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