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Several clefting factors have been implicated by studies in mouse models, while some of these have also been confirmed by genetic screening in humans. Here, we discuss several knockout mouse models to examine the role of specific genes in cleft formation. The cleft is ultimately caused by interference with shelf elevation, attachment, or fusion. Shelf elevation is brought about by mesenchymal proliferation and changes in the ECM induced by growth factors such as TGF-\u03b2s. Crucial ECM molecules are collagens, proteoglycans, and glycosaminoglycans. Shelf attachment depends on specific differentiation of the epithelium involving TGF-\u03b23, sonic hedgehog, and WNT signaling, and correct expression of epithelial adhesion molecules such as E-cadherin. The final fusion requires epithelial apoptosis and epithelium-to-mesenchyme transformation regulated by TGF-\u03b2 and WNT proteins. Other factors may interact with these signaling pathways and contribute to clefting. Normalization of the biological mechanisms regulating palatogenesis in susceptible fetuses is expected to contribute to cleft prevention.<\/jats:p>","DOI":"10.1177\/0022034508327868","type":"journal-article","created":{"date-parts":[[2009,1,8]],"date-time":"2009-01-08T19:39:42Z","timestamp":1231443582000},"page":"22-33","source":"Crossref","is-referenced-by-count":131,"title":["Biological Mechanisms in Palatogenesis and Cleft Palate"],"prefix":"10.1177","volume":"88","author":[{"given":"L.","family":"Meng","sequence":"first","affiliation":[{"name":"Department of Orthodontics and Oral Biology, Radboud University\r               Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands;"},{"name":"Key Laboratory for Oral Biomedical Engineering Ministry of Education,\r               School and Hospital of Stomatology, Wuhan University, Wuhan, P.R. China; and"},{"name":"Department of Tumor Immunology, Nijmegen Center for Molecular Life\r               Science, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Z.","family":"Bian","sequence":"additional","affiliation":[{"name":"Department of Orthodontics and Oral Biology, Radboud University\r               Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands;"},{"name":"Key Laboratory for Oral Biomedical Engineering Ministry of Education,\r               School and Hospital of Stomatology, Wuhan University, Wuhan, P.R. China; and"},{"name":"Department of Tumor Immunology, Nijmegen Center for Molecular Life\r               Science, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R.","family":"Torensma","sequence":"additional","affiliation":[{"name":"Department of Orthodontics and Oral Biology, Radboud University\r               Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands;"},{"name":"Key Laboratory for Oral Biomedical Engineering Ministry of Education,\r               School and Hospital of Stomatology, Wuhan University, Wuhan, P.R. China; and"},{"name":"Department of Tumor Immunology, Nijmegen Center for Molecular Life\r               Science, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.W.","family":"Von den Hoff","sequence":"additional","affiliation":[{"name":"Department of Orthodontics and Oral Biology, Radboud University\r               Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands;"},{"name":"Key Laboratory for Oral Biomedical Engineering Ministry of Education,\r               School and Hospital of Stomatology, Wuhan University, Wuhan, P.R. China; and"},{"name":"Department of Tumor Immunology, Nijmegen Center for Molecular Life\r               Science, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2009,1,1]]},"reference":[{"key":"bibr-ABBOTT-ETAL-2003","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/71.1.84"},{"key":"bibr-ABBOTT-ETAL-2005A","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.20117"},{"key":"bibr-ABBOTT-ETAL-2005B","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.20133"},{"key":"bibr-ALAPPAT-ETAL-2003","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cr.7290185"},{"key":"bibr-ALAPPAT-ETAL-2005","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2004.09.010"},{"key":"bibr-AMINI-NIK-ETAL-2007","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2007.05.024"},{"key":"bibr-ANTONY-2007","doi-asserted-by":"publisher","DOI":"10.1093\/ajcn\/85.2.598S"},{"key":"bibr-ARAYA-ETAL-2006","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2006.060049"},{"key":"bibr-ATASOY-ETAL-2007","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0611003104"},{"key":"bibr-AVILA-ETAL-2006","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.31367"},{"key":"bibr-BAATOUT-ETAL-2002","unstructured":"Baatout S, Jacquet P, Michaux A, Buset J, Vankerkom J,\n               Derradji H\n                      , et al.\n                      (2002). 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