{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T16:08:37Z","timestamp":1778170117195,"version":"3.51.4"},"reference-count":73,"publisher":"The Company of Biologists","license":[{"start":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T00:00:00Z","timestamp":1621296000000},"content-version":"am","delay-in-days":2694,"URL":"http:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Failure of facial prominence fusion causes cleft lip and palate (CL\/P), a common human birth defect. Currently there are two major hypotheses to explain cleft occurrence. The first holds that the epithelium at these locations is somehow defective for fusion while the second is that the prominences are dysplastic and unable to appose and fuse. Here, using geometric morphometrics, we analyzed facial outgrowth and shape change over time in a novel mouse model exhibiting fully penetrant bilateral CL\/P. This robust model is based upon mutations in Tfap2a, the gene encoding transcription factor AP-2\u03b1, which has been implicated in both syndromic and non-syndromic human CL\/P. Our findings indicate that aberrant morphology and subsequent misalignment of the facial prominences underlies the inability of the mutant prominences to fuse. Exencephaly also occurs in some of the Tfap2a mutants and we observe additional morphometric differences that indicate an influence of neural tube closure defects on facial shape. Molecular analysis of the CL\/P model indicates that Fgf signaling is misregulated in the face, and that reducing Fgf8 gene dosage can attenuate the clefting pathology by generating compensatory changes. Further, mutations in either Tfap2a or Fgf8 increase variance in facial shape, but the combination of these mutations restores variance to normal levels. The alterations in variance provide a potential mechanistic link between clefting and the evolution and diversity of facial morphology. Overall, our findings suggest that CL\/P can result from small gene expression changes that alter the shape of the facial prominences and uncouple their coordinated morphogenesis, which is necessary for normal fusion.<\/jats:p>","DOI":"10.1242\/dmm.017616","type":"journal-article","created":{"date-parts":[[2014,11,8]],"date-time":"2014-11-08T06:39:05Z","timestamp":1415428745000},"source":"Crossref","is-referenced-by-count":35,"title":["<i>Tfap2a<\/i>-dependent changes in facial morphology result in clefting that can be ameliorated by a reduction in<i>Fgf8<\/i>gene dosage"],"prefix":"10.1242","author":[{"given":"Rebecca M.","family":"Green","sequence":"first","affiliation":[{"name":"University of Colorado Denver, Aurora, CO, USA;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weiguo","family":"Feng","sequence":"additional","affiliation":[{"name":"University of Colorado Denver, Aurora, CO, USA;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tzulip","family":"Phang","sequence":"additional","affiliation":[{"name":"University of Colorado Denver, Aurora, CO, USA;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6943-0426","authenticated-orcid":false,"given":"Jennifer L.","family":"Fish","sequence":"additional","affiliation":[{"name":"UCSF, San Francisco, CA, USA;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong","family":"Li","sequence":"additional","affiliation":[{"name":"University of Colorado Denver, Aurora, CO, USA;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard A.","family":"Spritz","sequence":"additional","affiliation":[{"name":"University of Colorado Denver, Aurora, CO, USA;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ralph S.","family":"Marcucio","sequence":"additional","affiliation":[{"name":"UCSF, San Francisco, CA, USA;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joan","family":"Hooper","sequence":"additional","affiliation":[{"name":"University of Colorado Denver, Aurora, CO, USA;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heather","family":"Jamniczky","sequence":"additional","affiliation":[{"name":"University of Calgary, AB, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benedikt","family":"Hallgr\u00edmsson","sequence":"additional","affiliation":[{"name":"University of Calgary, AB, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Trevor","family":"Williams","sequence":"additional","affiliation":[{"name":"University of Colorado Denver, Aurora, CO, USA;"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"237","published-online":{"date-parts":[[2014,1,1]]},"reference":[{"key":"2021042501171914500_b1-0080031","doi-asserted-by":"crossref","first-page":"e1000420","DOI":"10.1371\/journal.pbio.1000420","article-title":"The role of spatially controlled cell proliferation in limb bud morphogenesis","volume":"8","author":"Boehm","year":"2010","journal-title":"PLoS Biol."},{"key":"2021042501171914500_b2-0080031","volume-title":"Morphometric Tools for Landmark Data","author":"Bookstein","year":"1997"},{"key":"2021042501171914500_b3-0080031","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/j.ydbio.2003.11.021","article-title":"Loss of AP-2alpha impacts multiple aspects of ventral body wall development and closure","volume":"267","author":"Brewer","year":"2004","journal-title":"Dev. 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