Embryogenetics of Cleft Lip and Palate

  • Geoffrey H. Sperber
  • Steven M. Sperber


The etiology of clefting of the labiopalatal ensemble that constitutes the central complex of the entrance to the oral cavity is best understood from the developmental phenomena creating the human face. Among the possible causes of clefts are single gene disorders, chromosome aberrations, teratogen exposure, and many as yet unknown sporadic events illustrating the complexity of facial patterning. Midface morphogenesis is a small component of the entire embryogenetic process but is critically important in determining cheiloschisis (cleft lip) and palatoschisis (cleft palate). Understanding the embryology of lip and palate development will provide insights into the multifactorial causes of clefting and possible prognostic, preventive, and treatment regimens.


Neural Crest Pharyngeal Arch Palatal Shelf Cranial Neural Crest Orofacial Cleft 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Abu-Hussein M (2012) Cleft lip and palate - etiological factors. Dental and Medical Problems 49:149–156Google Scholar
  2. Alappat SR, Zhang Z, Suzuki K, Zhang X, Liu H, Jiang R, Yamada G, Chen Y (2005) The cellular and molecular etiology of the cleft secondary palate in Fgf10 mutant mice. Dev Biol 277:102–113PubMedGoogle Scholar
  3. Andreou AM, Pauws E, Jones MC, Singh MK, Bussen M, Doudney K, Moore GE, Kispert A, Brosens JJ, Stanier P (2007) TBX22 missense mutations found in patients with X-linked cleft palate affect DNA binding, sumoylation, and transcriptional repression. Am J Hum Genet 81:700–712PubMedGoogle Scholar
  4. Arnold WH, Rezwani T, Baric I (1998) Location and distribution of epithelial pearls and tooth buds in human fetuses with cleft lip and palate. Cleft Palate Craniofac J 35:359–365PubMedGoogle Scholar
  5. Ashique AM, Fu K, Richman JM (2002) Endogenous bone morphogenetic proteins regulate outgrowth and epithelial survival during avian lip fusion. Development 129:4647–4660PubMedGoogle Scholar
  6. Baek J-A, Lan Y, Liu H, Maltby KM, Mishina Y, Jiang R (2011) Bmpr1a signaling plays critical roles in palatal shelf growth and palatal bone formation. Dev Biol 350:520–531PubMedGoogle Scholar
  7. Baghestani S, Sadeghi N, Yavarian M, Alghasi H (2010) Lower lip pits in a patient with van der Woude syndrome. J Craniofac Surg 21:1380–1381PubMedGoogle Scholar
  8. Barrow JR, Capecchi MR (1999) Compensatory defects associated with mutations in Hoxa1 restore normal palatogenesis to Hoxa2 mutants. Development 126:5011–5026PubMedGoogle Scholar
  9. Basch ML, Bronner-Fraser M, Garcia-Castro MI (2006) Specification of the neural crest occurs during gastrulation and requires Pax7. Nature 441:218–222PubMedGoogle Scholar
  10. Betters E, Liu Y, Kjaeldgaard A, Sundström E, García-Castro MI (2010) Analysis of early human neural crest development. Dev Biol 344:578–592PubMedGoogle Scholar
  11. Birkeland AC, Larrabee Y, Kent DT, Flores C, Su GH, Lee JH, Haddad J Jr (2011) Novel IRF6 mutations in Honduran Van der Woude syndrome patients. Mol Med Rep 4:237–241PubMedGoogle Scholar
  12. Boehringer S, van der Lijn F, Liu F, Gunther M, Sinigerova S, Nowak S, Ludwig KU, Herberz R, Klein S, Hofman A, Uitterlinden AG, Niessen WJ, Breteler MMB, van der Lugt A, Wurtz RP, Nothen MM, Horsthemke B, Wieczorek D, Mangold E, Kayser M (2011) Genetic determination of human facial morphology: links between cleft-lips and normal variation. Eur J Hum Genet 19:1192–1197PubMedGoogle Scholar
  13. Britanova O, Depew MJ, Schwark M, Thomas BL, Miletich I, Sharpe P, Tarabykin V (2006) Satb2 haploinsufficiency phenocopies 2q32-q33 deletions, whereas loss suggests a fundamental role in the coordination of jaw development. Am J Hum Genet 79:668–678PubMedGoogle Scholar
  14. Brito LA, Cruz LA, Rocha KM, Barbara LK, Silva CBF, Bueno DF, Aguena M, Bertola DR, Franco D, Costa AM, Alonso N, Otto PA, Passos-Bueno MR (2011) Genetic contribution for non-syndromic cleft lip with or without cleft palate (NS CL/P) in different regions of Brazil and implications for association studies. Am J Med Genet A 155:1581–1587Google Scholar
  15. Bush JO, Jiang R (2012) Palatogenesis: morphogenetic and molecular mechanisms of secondary palate development. Development 139:231–243PubMedGoogle Scholar
  16. Cai J, Ash D, Kotch LE, Jabs EW, Attie-Bitach T, Auge J, Mattei G, Etchevers H, Vekemans M, Korshunova Y, Tidwell R, Messina DN, Winston JB, Lovett M (2005) Gene expression in pharyngeal arch 1 during human embryonic development. Hum Mol Genet 14:903–912PubMedGoogle Scholar
  17. Chiquet BT, Blanton SH, Burt A, Ma D, Stal S, Mulliken JB, Hecht JT (2008) Variation in WNT genes is associated with non-syndromic cleft lip with or without cleft palate. Hum Mol Genet 17:2212–2218PubMedGoogle Scholar
  18. Clouthier DE, Garcia E, Schilling TF (2010) Regulation of facial morphogenesis by endothelin signaling: insights from mice and fish. Am J Med Genet A 152A:2962–2973PubMedGoogle Scholar
  19. Cordero DR, Brugmann S, Chu Y, Bajpai R, Jame M, Helms JA (2011) Cranial neural crest cells on the move: their roles in craniofacial development. Am J Med Genet A 155A:270–279PubMedGoogle Scholar
  20. Cuervo R, Covarrubias L (2004) Death is the major fate of medial edge epithelial cells and the cause of basal lamina degradation during palatogenesis. Development 131:15–24PubMedGoogle Scholar
  21. De Robertis EM, Morita EA, Cho KW (1991) Gradient fields and homeobox genes. Development 112:669–678PubMedGoogle Scholar
  22. Derijcke A, Eerens A, Carels C (1996) The incidence of oral clefts: a review. Br J Oral Maxillofac Surg 34:488–494PubMedGoogle Scholar
  23. Ding H, Wu X, Bostrom H, Kim I, Wong N, Tsoi B, O’Rourke M, Koh GY, Soriano P, Betsholtz C, Hart TC, Marazita ML, Field LL, Tam PP, Nagy A (2004) A specific requirement for PDGF-C in palate formation and PDGFR-alpha signaling. Nat Genet 36:1111–1116PubMedGoogle Scholar
  24. Dixon J, Jones NC, Sandell LL, Jayasinghe SM, Crane J, Rey J-P, Dixon MJ, Trainor PA (2006) Tcof1/Treacle is required for neural crest cell formation and proliferation deficiencies that cause craniofacial abnormalities. Proc Natl Acad Sci 103:13403–13408PubMedGoogle Scholar
  25. Dixon MJ, Marazita ML, Beaty TH, Murray JC (2011) Cleft lip and palate: understanding genetic and environmental influences. Nat Rev Genet 12:167–178PubMedGoogle Scholar
  26. Eberhart JK, Swartz ME, Crump JG, Kimmel CB (2006) Early Hedgehog signaling from neural to oral epithelium organizes anterior craniofacial development. Development 133:1069–1077PubMedGoogle Scholar
  27. Eberhart JK, He X, Swartz ME, Yan Y-L, Song H, Boling TC, Kunerth AK, Walker MB, Kimmel CB, Postlethwait JH (2008) MicroRNA Mirn140 modulates Pdgf signaling during palatogenesis. Nat Genet 40:290–298PubMedGoogle Scholar
  28. Economou AD, Ohazama A, Porntaveetus T, Sharpe PT, Kondo S, Basson MA, Gritli-Linde A, Cobourne MT, Green JB (2012) Periodic stripe formation by a Turing mechanism operating at growth zones in the mammalian palate. Nat Genet 44(3):348–351PubMedGoogle Scholar
  29. Etoz OA, Etoz A (2009) Isolated lower lip fistulas in Van der Woude syndrome. J Craniofac Surg 20:1612–1614PubMedGoogle Scholar
  30. Farlie P, Moody SA (2011) Editorial. Genesis 49:161–162PubMedGoogle Scholar
  31. Feng W, Leach SM, Tipney H, Phang T, Geraci M, Spritz RA, Hunter LE, Williams T (2009) Spatial and temporal analysis of gene expression during growth and fusion of the mouse facial prominences. PLoS One 4:e8066PubMedGoogle Scholar
  32. Ferguson MWJ (1988) Palate development. Development 103:41–60PubMedGoogle Scholar
  33. Fitzpatrick DR, Denhez F, Kondaiah P, Akhurst RJ (1990) Differential expression of TGF beta isoforms in murine palatogenesis. Development 109:585–595PubMedGoogle Scholar
  34. FitzPatrick DR, Carr IM, McLaren L, Leek JP, Wightman P, Williamson K, Gautier P, McGill N, Hayward C, Firth H, Markham AF, Fantes JA, Bonthron DT (2003) Identification of SATB2 as the cleft palate gene on 2q32-q33. Hum Mol Genet 12:2491–2501PubMedGoogle Scholar
  35. Francis-West P, Robson L, Evans DJ (2003) Craniofacial development: the tissue and molecular interactions that control development of the head. Adv Anat Embryol Cell Biol 169:1–138Google Scholar
  36. Fraser FC (1976) The multifactorial/threshold concept – uses and misuses. Teratology 14:267–280PubMedGoogle Scholar
  37. Ghassibe-Sabbagh M, Desmyter L, Langenberg T, Claes F, Boute O, Bayet B, Pellerin P, Hermans K, Backx L, Mansilla MA, Imoehl S, Nowak S, Ludwig KU, Baluardo C, Ferrian M, Mossey PA, Noethen M, Dewerchin M, François G, Revencu N, Vanwijck R, Hecht J, Mangold E, Murray J, Rubini M, Vermeesch JR, Poirel HA, Carmeliet P, Vikkula M (2011) FAF1, a gene that is disrupted in cleft palate and has conserved function in zebrafish. Am J Hum Genet 88:150–161PubMedGoogle Scholar
  38. Greene RM, Pisano MM (2010) Palate morphogenesis: current understanding and future directions. Birth Defects Res C Embryo Today 90:133–154PubMedGoogle Scholar
  39. Hanson JW, Smith DW (1975) U-shaped palatal defect in the Robin anomalad: developmental and clinical relevance. J Pediatr 87:30–33PubMedGoogle Scholar
  40. Harvey W (1847) The works of William Harvey: translated from the Latin with a life of the author by R. Willis. The Sydenham Society, LondonGoogle Scholar
  41. Hay ED (2005) The mesenchymal cell, its role in the embryo, and the remarkable signaling mechanisms that create it. Dev Dyn 233:706–720PubMedGoogle Scholar
  42. Hilliard SA, Yu L, Gu S, Zhang Z, Chen YP (2005) Regional regulation of palatal growth and patterning along the anterior–posterior axis in mice. J Anat 207:655–667PubMedGoogle Scholar
  43. Hochheiser H, Aronow BJ, Artinger K, Beaty TH, Brinkley JF, Chai Y, Clouthier D, Cunningham ML, Dixon M, Donahue LR, Fraser SE, Hallgrimsson B, Iwata J, Klein O, Marazita ML, Murray JC, Murray S, de Villena FP, Postlethwait J, Potter S, Shapiro L, Spritz R, Visel A, Weinberg SM, Trainor PA (2011) The FaceBase Consortium: a comprehensive program to facilitate craniofacial research. Dev Biol 355:175–182PubMedGoogle Scholar
  44. Honkura T, Ogasawara J, Yamada T, Morishita S (2002) The Gene Resource Locator: gene locus maps for transcriptome analysis. Nucleic Acids Res 30:221–225PubMedGoogle Scholar
  45. Hu D, Marcucio RS (2009) A SHH-responsive signaling center in the forebrain regulates craniofacial morphogenesis via the facial ectoderm. Development 136:107–116PubMedGoogle Scholar
  46. Hu D, Marcucio RS, Helms JA (2003) A zone of frontonasal ectoderm regulates patterning and growth in the face. Development 130:1749–1758PubMedGoogle Scholar
  47. Huang X, Yokota T, Iwata J, Chai Y (2011) Tgf-β-mediated FasL-Fas-caspase pathway is crucial during palatogenesis. J Dent Res 90:981–987PubMedGoogle Scholar
  48. Ingraham CR, Kinoshita A, Kondo S, Yang B, Sajan S, Trout KJ, Malik MI, Dunnwald M, Goudy SL, Lovett M, Murray JC, Schutte BC (2006) Abnormal skin, limb and craniofacial morphogenesis in mice deficient for interferon regulatory factor 6 (Irf6). Nat Genet 38:1335–1340PubMedGoogle Scholar
  49. International Human Genome Sequencing Consortium (2004) Finishing the euchromatic sequence of the human genome. Nature 431:931–945Google Scholar
  50. Iordanskaia T, Nawshad A (2011) Mechanisms of transforming growth factor β induced cell cycle arrest in palate development. J Cell Physiol 226:1415–1424PubMedGoogle Scholar
  51. Iseki S (2011) Disintegration of the medial epithelial seam: is cell death important in palatogenesis? Dev Growth Differ 53(2):259–268PubMedGoogle Scholar
  52. Ito Y, Yeo JY, Chytil A, Han J, Bringas P Jr, Nakajima A, Shuler CF, Moses HL, Chai Y (2003) Conditional inactivation of Tgfbr2 in cranial neural crest causes cleft palate and calvaria defects. Development 130:5269–5280PubMedGoogle Scholar
  53. Iwata J, Parada C, Chai Y (2011) The mechanism of TGF-β signaling during palate development. Oral Dis 17:733–744PubMedGoogle Scholar
  54. Jagomagi T, Soots M, Saag M (2010) Epidemiologic factors causing cleft lip and palate and their regularities of occurrence in Estonia. Stomatologija 12:105–108PubMedGoogle Scholar
  55. Jezewski PA, Vieira AR, Nishimura C, Ludwig B, Johnson M, O’ Brien SE, Daack-Hirsch S, Schultz RE, Weber A, Nepomucena B, Romitti PA, Christensen K, Orioli IM, Castilla EE, Machida J, Natsume N, Murray JC (2003) Complete sequencing shows a role for MSX1 in non-syndromic cleft lip and palate. J Med Genet 40:399–407PubMedGoogle Scholar
  56. Jiang R, Lan Y, Chapman HD, Shawber C, Norton CR, Serreze DV, Weinmaster G, Gridley T (1998) Defects in limb, craniofacial, and thymic development in Jagged2 mutant mice. Genes Dev 12:1046–1057PubMedGoogle Scholar
  57. Jiang R, Bush JO, Lidral AC (2006) Development of the upper lip: morphogenetic and molecular mechanisms. Dev Dyn 235:1152–1166PubMedGoogle Scholar
  58. Jobling R, Ferrier RA, McLeod R, Petrin AL, Murray JC, Thomas MA (2011) Monozygotic twins with variable expression of Van der Woude syndrome. Am J Med Genet A 155:2008–2010Google Scholar
  59. Jones MC (2002) Prenatal diagnosis of cleft lip and palate: detection rates, accuracy of ultrasonography, associated anomalies, and strategies for counseling. Cleft Palate Craniofac J 39:169–173PubMedGoogle Scholar
  60. Kantaputra PN, Paramee M, Kaewkhampa A, Hoshino A, Lees M, McEntagart M, Masrour N, Moore GE, Pauws E, Stanier P (2011) Cleft lip with cleft palate, ankyloglossia, and hypodontia are associated with TBX22 mutations. J Dent Res 90:450–455PubMedGoogle Scholar
  61. Kondo S, Schutte BC, Richardson RJ, Bjork BC, Knight AS, Watanabe Y, Howard E, Ferreira de Lima RLL, Daack-Hirsch S, Sander A, McDonald-McGinn DM, Zackai EH, Lammer EJ, Aylsworth AS, Ardinger HH, Lidral AC, Pober BR, Moreno L, Arcos-Burgos M, Valencia C, Houdayer C, Bahuau M, Moretti-Ferreira D, Richieri-Costa A, Dixon MJ, Murray JC (2002) Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes. Nat Genet 32:285–289PubMedGoogle Scholar
  62. Krapels IP, Vermeij-Keers C, Müller M, de Klein A, Steegers-Theunissen RP (2006) Nutrition and genes in the development of orofacial clefting. Nutr Rev 64:280–288PubMedGoogle Scholar
  63. Lan Y, Ovitt CE, Cho E-S, Maltby KM, Wang Q, Jiang R (2004) Odd-skipped related 2 (Osr2) encodes a key intrinsic regulator of secondary palate growth and morphogenesis. Development 131:3207–3216PubMedGoogle Scholar
  64. Landes CA, Weichert F, Geis P, Helga F, Wagner M (2006) Evaluation of two 3D virtual computer reconstructions for comparison of cleft lip and palate to normal fetal microanatomy. Anat Rec A Discov Mol Cell Evol Biol 288A:248–262Google Scholar
  65. Larsen KB, Lutterodt MC, Møllgård K, Møller M (2010) Expression of the homeobox genes OTX2 and OTX1 in the early developing human brain. J Histochem Cytochem 58:669–678PubMedGoogle Scholar
  66. Larson BJ, Longaker MT, Lorenz HP (2010) Scarless fetal wound healing: a basic science review. Plast Reconstr Surg 126:1172–1180PubMedGoogle Scholar
  67. Le Douarin NM, Creuzet S, Couly G, Dupin E (2004) Neural crest cell plasticity and its limits. Development 131:4637–4650PubMedGoogle Scholar
  68. Letra A, Menezes R, Cooper ME, Fonseca RF, Tropp S, Govil M, Granjeiro JM, Imoehl SR, Mansilla MA, Murray JC, Castilla EE, Orioli IM, Czeizel AE, Ma L, Chiquet BT, Hecht JT, Vieira AR, Marazita ML (2011) CRISPLD2 variants including a C471T silent mutation may contribute to nonsyndromic cleft lip with or without cleft palate. Cleft Palate Craniofac J 48:363–370PubMedGoogle Scholar
  69. Levi B, James AW, Nelson ER, Brugmann SA, Sorkin M, Manu A, Longaker MT (2011) Role of Indian hedgehog signaling in palatal osteogenesis. Plast Reconstr Surg 127:1182–1190PubMedGoogle Scholar
  70. Li L, Meng T, Jia Z, Zhu G, Shi B (2010) Single nucleotide polymorphism associated with nonsyndromic cleft palate influences the processing of miR-140. Am J Med Genet A 152A:856–862PubMedGoogle Scholar
  71. Lidral AC, Romitti PA, Basart AM, Doetschman T, Leysens NJ, Daack-Hirsch S, Semina EV, Johnson LR, Machida J, Burds A, Parnell TJ, Rubenstein JLR, Murray JC (1998) Association of MSX1 and TGFB3 with nonsyndromic clefting in humans. Am J Hum Genet 63:557–568PubMedGoogle Scholar
  72. Lin C, Fisher AV, Yin Y, Maruyama T, Veith GM, Dhandha M, Huang GJ, Hsu W, Ma L (2011) The inductive role of Wnt-β-Catenin signaling in the formation of oral apparatus. Dev Biol 356:40–50PubMedGoogle Scholar
  73. Liou J-D, Huang Y-H, Hung T-H, Hsieh C-L, Hsieh TT, Lo L-M (2011) Prenatal diagnostic rates and postnatal outcomes of fetal orofacial clefts in a Taiwanese population. Int J Gynaecol Obstet 113Google Scholar
  74. Liu W, Sun X, Braut A, Mishina Y, Behringer RR, Mina M, Martin JF (2005) Distinct functions for Bmp signaling in lip and palate fusion in mice. Development 132:1453–1461PubMedGoogle Scholar
  75. Liu B, Rooker SM, Helms JA (2010) Molecular control of facial morphology. Semin Cell Dev Biol 21:309–313PubMedGoogle Scholar
  76. Liu F, Van Der Lijn F, Schurmann C et al. (2012) A genome-wide association identifies five loci influencing facial morphology in Europeans. PLoS Genet 8(9):e1002923Google Scholar
  77. Losee J, Kirschner R (2009) Comprehensive cleft care. McGraw-Hill, New York. ISBN 007148180xGoogle Scholar
  78. Ludwig KU, Mangold E, Herms S et al. (2012) Evaluating SKI as a candidate gene for non-syndromic cleft lip with or without cleft palate. Nat Genet 44(9):968–971Google Scholar
  79. Luijsterburg AJM, Vermeij-Keers C (2011) Ten years recording common oral clefts with a new descriptive system. Cleft Palate Craniofac J 48:173–182PubMedGoogle Scholar
  80. Mangold E, Reutter H, León-Cachón RB, Ludwig KU, Herms S, Chacón-Camacho O, Ortiz-López R, Paredes-Zenteno M, Arizpe-Cantú A, Muñoz-Jiménez SG, Nowak S, Kramer FJ, Wienker TF, Nöthen MM, Knapp M, Rojas-Martínez A (2012) Evaluating SKI as a candidate gene for non-syndromic cleft lip with or without cleft palate. Eur J Oral Sci 120(5):373–377Google Scholar
  81. Mansouri Hattab N, Lahmiti S, Bouaichi A, Hiroual A, El Bouihi M, Fikry T (2011) Les fentes labio-palatines médianes: un diagnostic qui en cache un autre. Arch Pediatr 18:149–152PubMedGoogle Scholar
  82. Marcucio RS, Young NM, Hu D, Hallgrimsson B (2011) Mechanisms that underlie co-variation of the brain and face. Genesis 49:177–189PubMedGoogle Scholar
  83. Meng L, Bian Z, Torensma R, Von den Hoff JW (2009) Biological mechanisms in palatogenesis and cleft palate. J Dent Res 88(1):22–33Google Scholar
  84. Mossey P (2007) Epidemiology underpinning research in the aetiology of orofacial clefts. Orthod Craniofac Res 10:114–120PubMedGoogle Scholar
  85. Mossey P, Little J (2002) Epidemiology of oral clefts: an international perspective. Oxford University Press, OxfordGoogle Scholar
  86. Mostowska A, Hozyasz KK, Biedziak B, Wojcicki P, Lianeri M, Jagodzinski PP (2012) Genotype and haplotype analysis of WNT genes in non-syndromic cleft lip with or without cleft palate. Eur J Oral Sci 120:1–8PubMedGoogle Scholar
  87. Nakajima A, Tanaka E, Ito Y, Maeno M, Iwata K, Shimizu N, Shuler CF (2010) The expression of TGF-β3 for epithelial-mesenchyme transdifferentiated MEE in palatogenesis. J Mol Histol 41(6):343–355PubMedGoogle Scholar
  88. Nakamura Y, Yamamoto K, He X, Otsuki B, Kim Y, Murao H, Soeda T, Tsumaki N, Deng JM, Zhang Z, Behringer RR, Crombrugghe B, Postlethwait JH, Warman ML, Nakamura T, Akiyama H (2011) Wwp2 is essential for palatogenesis mediated by the interaction between Sox9 and mediator subunit 25. Nat Commun 2:251PubMedGoogle Scholar
  89. Nakatomi M, Wang X-P, Key D, Lund JJ, Turbe-Doan A, Kist R, Aw A, Chen Y, Maas RL, Peters H (2010) Genetic interactions between Pax9 and Msx1 regulate lip development and several stages of tooth morphogenesis. Dev Biol 340:438–449PubMedGoogle Scholar
  90. Nelson ER, Levi B, Sorkin M, James AW, Liu KJ, Quarto N, Longaker MT (2011) Role of GSK-3β in the osteogenic differentiation of palatal mesenchyme. PLoS One 6(10):e25847PubMedGoogle Scholar
  91. Ng SB, Bigham AW, Buckingham KJ, Hannibal MC, McMillin MJ, Gildersleeve HI, Beck AE, Tabor HK, Cooper GM, Mefford HC, Lee C, Turner EH, Smith JD, Rieder MJ, Yoshiura K, Matsumoto N, Ohta T, Niikawa N, Nickerson DA, Bamshad MJ, Shendure J (2010) Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nat Genet 42:790–793PubMedGoogle Scholar
  92. Nielsen R (2010) Genomics: in search of rare human variants. Nature 467:1050–1051PubMedGoogle Scholar
  93. Noden DM, Francis-West P (2006) The differentiation and morphogenesis of craniofacial muscles. Dev Dyn 235:1194–1218PubMedGoogle Scholar
  94. Noden DM, Trainor PA (2005) Relations and interactions between cranial mesoderm and neural crest populations. J Anat 207:575–601PubMedGoogle Scholar
  95. Nunzi M-G, Pisarek A, Mugnaini E (2004) Merkel cells, corpuscular nerve endings and free nerve endings in the mouse palatine mucosa express three subtypes of vesicular glutamate transporters. J Neurocytol 33:359–376PubMedGoogle Scholar
  96. Odent S, Attié-Bitach T, Blayau M, Mathieu M, Augé J, Delezoïde AL, Le Gall JY, Le Marec B, Munnich A, David V, Vekemans M (1999) Expression of the sonic hedgehog (SHH) gene during early human development and phenotypic expression of new mutations causing holoprosencephaly. Hum Mol Genet 8:1683–1689PubMedGoogle Scholar
  97. Oka K, Honda MJ, Tsuruga E, Hatakeyama Y, Isokawa K, Sawa Y (2012) Roles of collagen and periostin expression by cranial neural crest cells during soft palate development. J Histochem Cytochem 60(1):57–68PubMedGoogle Scholar
  98. Oliveira DT, Odell EW (1997) Expression of CD44 variant exons by normal oral epithelia. Oral Oncol 33:260–262PubMedGoogle Scholar
  99. Oostra RJ, de Rooij L, Stevenson RE (2004) Willem Vrolik and the tabulae (with appendices). In: Vrolik W (ed) Tabulae illustrating normal and abnormal development in man and mammals. Greenwood Genetic Center-Keys Printing, GreenvilleGoogle Scholar
  100. Paiva KBS, Silva-Valenzuela MG, Massironi SMG, Ko GM, Siqueira FM, Nunes FD (2010) Differential Shh, Bmp and Wnt gene expressions during craniofacial development in mice. Acta Histochem 112:508–517PubMedGoogle Scholar
  101. Pantalacci S, Prochazka J, Martin A, Rothova M, Lambert A, Bernard L, Charles C, Viriot L, Peterkova R, Laudet V (2008) Patterning of palatal rugae through sequential addition reveals an anterior/posterior boundary in palatal development. BMC Dev Biol 8:116PubMedGoogle Scholar
  102. Peters H, Neubüser A, Kratochwil K, Balling R (1998) Pax9-deficient mice lack pharyngeal pouch derivatives and teeth and exhibit craniofacial and limb abnormalities. Genes Dev 12:2735–2747PubMedGoogle Scholar
  103. Piotrowski A, Woźniak W, Bruska M (2011) Early development of the human palate in stages 16 and 17. Folia Morphol (Warsz) 70(1):29–32Google Scholar
  104. Porntaveetus T, Oommen S, Sharpe PT, Ohazama A (2010) Expression of Fgf signalling pathway related genes during palatal rugae development in the mouse. Gene Expr Patterns 10:193–198PubMedGoogle Scholar
  105. Radlanski RJ, Renz H (2006) Genes, forces, and forms: mechanical aspects of prenatal craniofacial development. Dev Dyn 235:1219–1229PubMedGoogle Scholar
  106. Rahimov F, Jugessur A, Murray JC (2011) Genetics of nonsyndromic orofacial clefts. Cleft Palate Craniofac J 49:73–91PubMedGoogle Scholar
  107. Reid BS, Yang H, Melvin VS, Taketo MM, Williams T (2011) Ectodermal WNT/β-catenin signaling shapes the mouse face. Dev Biol 349:261–269PubMedGoogle Scholar
  108. Reiter R, Brosch S, Ludeke M, Fischbein E, Hasse S, Pickard A, Assum G, Schwandt A, Vogel W, Hogel J, Maier C (2012) Genetic and environmental risk factors for submucous cleft palate. Eur J Oral Sci 120:97–103PubMedGoogle Scholar
  109. Rice R, Spencer-Dene B, Connor EC, Gritli-Linde A, McMahon AP, Dickson C, Thesleff I, Rice DPC (2004) Disruption of Fgf10/Fgfr2b-coordinated epithelial-mesenchymal interactions causes cleft palate. J Clin Invest 113:1692–1700PubMedGoogle Scholar
  110. Richardson RJ, Dixon J, Malhotra S, Hardman MJ, Knowles L, Boot-Handford RP, Shore P, Whitmarsh A, Dixon MJ (2006) Irf6 is a key determinant of the keratinocyte proliferation-differentiation switch. Nat Genet 38:1329–1334PubMedGoogle Scholar
  111. Rorick NK, Kinoshita A, Weirather JL, Peyrard-Janvid M, de Lima RLLF, Dunnwald M, Shanske AL, Moretti-Ferreira D, Koillinen H, Kere J, Mansilla MA, Murray JC, Goudy SL, Schutte BC (2011) Genomic strategy identifies a missense mutation in WD-repeat domain 65 (WDR65) in an individual with Van der Woude syndrome. Am J Med Genet A 155:1314–1321Google Scholar
  112. San Miguel S, Serrano MJ, Sachar A, Henkemeyer M, Svoboda KKH, Benson MD (2011) Ephrin reverse signaling controls palate fusion via a PI3 kinase-dependent mechanism. Dev Dyn 240:357–364PubMedGoogle Scholar
  113. Sasaki Y, Tanaka S, Hamachi T, Taya Y (2004) Deficient cell proliferation in palatal shelf mesenchyme of CL/Fr mouse embryos. J Dent Res 83:797–801PubMedGoogle Scholar
  114. Scheller EL, Krebsbach PH (2009) Gene therapy: design and prospects for craniofacial regeneration. J Dent Res 88:585–596PubMedGoogle Scholar
  115. Shaw JH et al (1978) Textbook of oral biology. W.B. Saunders Co, PhiladelphiaGoogle Scholar
  116. Shi M, Mostowska A, Jugessur A, Johnson MK, Mansilla MA, Christensen K, Lie RT, Wilcox AJ, Murray JC (2009) Identification of microdeletions in candidate genes for cleft lip and/or palate. Birth Defects Res A Clin Mol Teratol 85:42–51PubMedGoogle Scholar
  117. Smith A, Graham A (2001) Restricting Bmp-4 mediated apoptosis in hindbrain neural crest. Dev Dyn 220:276–283PubMedGoogle Scholar
  118. Snyder-Warwick AK, Perlyn CA (2012) Coordinated events; FGF signaling and other related pathways in palatogenesis. J Craniofac Surg 23:397–400Google Scholar
  119. Sohn WJ, Yamamoto H, Shin HI, Ryoo ZY, Lee S, Bae YC, Jung HS, Kim JY (2011) Importance of region-specific epithelial rearrangements in mouse rugae development. Cell Tissue Res 344(2):271–277PubMedGoogle Scholar
  120. Spears R, Svoboda KKH (2005) Growth factors and signaling proteins in craniofacial development. Semin Orthod 11:184–198Google Scholar
  121. Sperber GH (2006) New insights in facial development. Semin Orthod 12:4–10Google Scholar
  122. Sperber GH, Sperber SM, Guttmann GD (2010) Craniofacial embryogenetics and development, 2nd edn. People’s Medical Publishing House USA, SheltonGoogle Scholar
  123. Stanier P, Moore GE (2004) Genetics of cleft lip and palate: syndromic genes contribute to the incidence of non-syndromic clefts. Hum Mol Genet 13:R73–R81PubMedGoogle Scholar
  124. Stoll C, Clementi M (2003) Prenatal diagnosis of dysmorphic syndromes by routine fetal ultrasound examination across Europe. Ultrasound Obstet Gynecol 21:543–551PubMedGoogle Scholar
  125. Stuppia L, Capogreco M, Marzo G, La Rovere D, Antonucci I, Gatta V, Palka G, Mortellaro C, Tetè S (2011) Genetics of syndromic and nonsyndromic cleft lip and palate. J Craniofac Surg 22:1722–1726PubMedGoogle Scholar
  126. Swartz ME, Sheehan-Rooney K, Dixon MJ, Eberhart JK (2011) Examination of a palatogenic gene program in zebrafish. Dev Dyn 240:2204–2220PubMedGoogle Scholar
  127. Szabo-Rogers HL, Geetha-Loganathan P, Nimmagadda S, Fu KK, Richman JM (2008) FGF signals from the nasal pit are necessary for normal facial morphogenesis. Dev Biol 318:289–302PubMedGoogle Scholar
  128. Szabo-Rogers HL, Smithers LE, Yakob W, Liu KJ (2010) New directions in craniofacial morphogenesis. Dev Biol 341:84–94PubMedGoogle Scholar
  129. Tonni G, Lituania M (2012) OmniView algorithm: a novel 3-dimensional sonographic technique in the study of the fetal hard and soft palates. J Ultrasound Med 31(2):313–318PubMedGoogle Scholar
  130. van den Boogaard M-JH, Dorland M, Beemer FA, van Amstel HKP (2000) MSX1 mutation is associated with orofacial clefting and tooth agenesis in humans. Nat Genet 24:342–343PubMedGoogle Scholar
  131. Vaziri Sani F, Hallberg K, Harfe BD, McMahon AP, Linde A, Gritli-Linde A (2005) Fate-mapping of the epithelial seam during palatal fusion rules out epithelial-mesenchymal transformation. Dev Biol 285:490–495PubMedGoogle Scholar
  132. Vieille-Grosjean I, Hunt P, Gulisano M, Boncinelli E, Thorogood P (1997) Branchial HOX gene expression and human craniofacial development. Dev Biol 183:49–60PubMedGoogle Scholar
  133. Vukojevic K, Kero D, Novakovic J, Kalibovic Govorko D, Saraga-Babic M. (2012) Cell proliferation and apoptosis in the fusion of the human primary and secondary palates. Eur J Oral Sci 120:283–291Google Scholar
  134. Wallace GH, Arellano JM, Gruner TM (2011) Non-syndromic cleft lip and palate: could stress be a causal factor? Women Birth 24:40–46PubMedGoogle Scholar
  135. Wang G, Shan R, Zhao L, Zhu X, Zhang X (2011) Fetal cleft lip with and without cleft palate: comparison between MR imaging and US for prenatal diagnosis. Eur J Radiol 79:437–442PubMedGoogle Scholar
  136. Weatherley-White RC, Ben S, Jin Y, Riccardi S, Arnold TD, Spritz RA (2011) Analysis of genomewide association signals for nonsyndromic cleft lip/palate in a Kenya African cohort. Am J Med Genet A 155:2422–2425Google Scholar
  137. Wehby G, Jugessur A, Murray J, Moreno L, Wilcox A, Lie R (2011) Genes as instruments for studying risk behavior effects: an application to maternal smoking and orofacial clefts. Health Serv Outcomes Res Methodol 11:54–78PubMedGoogle Scholar
  138. Welsh IC, O’Brien TP (2009) Signaling integration in the rugae growth zone directs sequential SHH signaling center formation during the rostral outgrowth of the palate. Dev Biol 336:53–67PubMedGoogle Scholar
  139. Welsh IC, Hagge-Greenberg A, O’Brien TP (2007) A dosage-dependent role for Spry2 in growth and ­patterning during palate development. Mech Dev 124:746–761PubMedGoogle Scholar
  140. Widera D, Zander C, Heidbreder M, Kasperek Y, Noll T, Seitz O, Saldamli B, Sudhoff H, Sader R, Kaltschmidt C, Kaltschmidt B (2009) Adult palatum as a novel source of neural crest-related stem cells. Stem Cells 27:1899–1910PubMedGoogle Scholar
  141. Wilkie AO, Morriss-Kay GM (2001) Genetics of craniofacial development and malformation. Nat Rev Genet 2:458–468PubMedGoogle Scholar
  142. Wu T, Fallin MD, Shi M, Ruczinski I, Liang KY, Hetmanski JB, Wang H, Ingersoll RG, Huang S, Ye X, Wu-Chou YH, Chen PK, Jabs EW, Shi B, Redett R, Scott AF, Murray JC, Marazita ML, Munger RG, Beaty TH (2012) Evidence of gene-environment interaction for the RUNX2 gene and environmental tobacco smoke in controlling the risk of cleft lip with/without cleft palate. Birth Defects Res A Clin Mol Teratol 94(2):76–83PubMedGoogle Scholar
  143. Xiong W, He F, Morikawa Y, Yu X, Zhang Z, Lan Y, Jiang R, Cserjesi P, Chen Y (2009) Hand2 is required in the epithelium for palatogenesis in mice. Dev Biol 330:131–141PubMedGoogle Scholar
  144. Xu J, Krebs LT, Gridley T (2010) Generation of mice with a conditional null allele of the Jagged2 gene. Genesis 48:390–393PubMedGoogle Scholar
  145. Yu K, Ornitz DM (2011) Histomorphological study of palatal shelf elevation during murine secondary palate formation. Dev Dyn 240:1737–1744PubMedGoogle Scholar
  146. Yu L, Gu S, Alappat S, Song Y, Yan M, Zhang X, Zhang G, Jiang Y, Zhang Z, Zhang Y, Chen Y (2005) Shox2-deficient mice exhibit a rare type of incomplete clefting of the secondary palate. Development 132:4397–4406PubMedGoogle Scholar
  147. Yuan Q, Blanton SH, Hecht JT (2011) Genetic causes of nonsyndromic cleft lip with or without cleft palate. Adv Otorhinolaryngol 70:107–113PubMedGoogle Scholar
  148. Zhang Z, Song Y, Zhao X, Zhang X, Fermin C, Chen Y (2002) Rescue of cleft palate in Msx1-deficient mice by transgenic Bmp4 reveals a network of BMP and Shh signaling in the regulation of mammalian palatogenesis. Development 129:4135–4146PubMedGoogle Scholar
  149. Zhang B, Jiao X, Mao L, Xue J (2011a) Maternal cigarette smoking and the associated risk of having a child with orofacial clefts in China: a case–control study. J Craniomaxillofac Surg 39:313–318PubMedGoogle Scholar
  150. Zhang J, Tu Q, Grosschedl R, Kim MS, Griffin T, Drissi H, Yang P, Chen J (2011b) Roles of SATB2 in osteogenic differentiation and bone regeneration. Tissue Eng Part A 17:1767–1776PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.Faculty of Medicine and DentistryEdmonton Clinic Health Academy, University of AlbertaEdmontonCanada
  2. 2.Denver Genetic Laboratories, Department of Pediatrics, School of MedicineUniversity of ColoradoAuroraUSA

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