{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T23:04:27Z","timestamp":1784329467795,"version":"3.55.0"},"reference-count":67,"publisher":"Societatea Romana de Morfologie","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Rom J Morphol Embryol"],"published-print":{"date-parts":[[2026,7,10]]},"abstract":"<jats:p>Cleft of the lip associated with or unassociated with cleft of the palate and cleft palate (CLP) represent frequent birth defects, and the mechanisms by which they occur are not completely clear. On the other hand, knowledge of the normal mechanisms underlying lip development and palatogenesis is still incomplete, and therefore a better understanding and consolidation of our knowledge in this field could help to study these deformities. Upper lip and secondary palate formation are complex processes, involving the subtle integration of several biological events, the disruption of which causes the clefting phenotype. Indeed, these developmental events imply a series of morphogenetic changes involving concerted cell survival, migration, growth, pattern generation, modulation of adhesiveness, death and differentiation. In recent years, genetically engineered animal models and in vitro palate cultures have greatly advanced our knowledge of the cellular and molecular pathways underlying normal orofacial morphogenesis, and abnormally developed CLP as well. Indeed, most of the morphogenetic events of craniofacial development are highly conserved amongst vertebrates, therefore animal models have revealed major insights into the mechanisms that take place in human orofacial development. Given their complexity, it is easy to imagine that the failure of the highly coordinated processes that guide the union of the lip and palate causes various forms of clefts. This article provides an overview of the embryological development of the lip and secondary palate, as well as the mechanisms underlying deviant development resulting in CLP, concentrating on the cellular and molecular characteristics.<\/jats:p>","DOI":"10.47162\/rjme.67.1.05","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T22:55:06Z","timestamp":1784328906000},"page":"53-62","source":"Crossref","is-referenced-by-count":0,"title":["Cleft lip\/palate. From embryology to developmental pathogenesis"],"prefix":"10.47162","volume":"67","author":[{"name":"Department of Anatomical Pathology, Hospital of Vimercate, Italy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcello","family":"Guarino","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"26736","published-online":{"date-parts":[[2026,7,2]]},"reference":[{"key":"ref0","doi-asserted-by":"publisher","unstructured":"\"[1] Dixon MJ, Marazita ML, Beaty TH, Murray JC. Cleft lip and palate: understanding genetic and environmental influences. Nat Rev Genet, 2011, 12(3):167-178. https:\/\/doi.org\/10.1038\/nrg2933","DOI":"10.1038\/nrg2933"},{"key":"ref1","unstructured":"[2] Ferguson MW. The orofacial region. In: Wigglesworth JS, Singer DB (eds). Textbook of fetal and perinatal pathology. 2nd edition, Blackwell Scientific Publications, Malden, MA, USA, 1998, 843-880."},{"key":"ref2","doi-asserted-by":"publisher","unstructured":"[3] Kousa YA, Schutte BC. Toward an orofacial gene regulatory network. Dev Dyn, 2016, 245(3):220-232. https:\/\/doi.org\/10.1002\/dvdy.24341","DOI":"10.1002\/dvdy.24341"},{"key":"ref3","doi-asserted-by":"publisher","unstructured":"[4] Meng L, Bian Z, Torensma R, Von den Hoff JW. Biological mechanisms in palatogenesis and cleft palate. J Dent Res, 2009, 88(1):22-33. https:\/\/doi.org\/10.1177\/0022034508327868","DOI":"10.1177\/0022034508327868"},{"key":"ref4","doi-asserted-by":"publisher","unstructured":"[5] Paiva KBS, Maas CS, Dos Santos PM, Granjeiro JM, Letra A. Extracellular matrix composition and remodeling: current perspectives on secondary palate formation, cleft lip\/palate, and palatal reconstruction. Front Cell Dev Biol, 2019, 7:340. https:\/\/doi.org\/10.3389\/fcell.2019.00340","DOI":"10.3389\/fcell.2019.00340"},{"key":"ref5","doi-asserted-by":"publisher","unstructured":"[6] Samanich J. Cleft palate. Pediatr Rev, 2009, 30(6):230-232. https:\/\/doi.org\/10.1542\/pir.30-6-230","DOI":"10.1542\/pir.30-6-230"},{"key":"ref6","doi-asserted-by":"publisher","unstructured":"[7] Ferguson MW. Palate development. Development, 1988, 103(Suppl):41-60. https:\/\/doi.org\/10.1242\/dev.103.Supplement.41","DOI":"10.1242\/dev.103.Supplement.41"},{"key":"ref7","doi-asserted-by":"publisher","unstructured":"[8] Mossey PA, Little J, Munger RG, Dixon MJ. Shaw WC. Cleft lip and palate. Lancet, 2009, 374(9703):1773-1785. https:\/\/doi.org\/10.1016\/s0140-6736(09)60695-4","DOI":"10.1016\/S0140-6736(09)60695-4"},{"key":"ref8","doi-asserted-by":"publisher","unstructured":"[9] Murray JC. Gene\/environment causes of cleft lip and\/or palate. Clin Genet, 2002, 61(4):248-256. https:\/\/doi.org\/10.1034\/j.1399-0004.2002.610402.x","DOI":"10.1034\/j.1399-0004.2002.610402.x"},{"key":"ref9","doi-asserted-by":"publisher","unstructured":"[10] Marazita ML. The evolution of human genetic studies of cleft lip and cleft palate. Annu Rev Genomics Hum Genet, 2012, 13:263-283. https:\/\/doi.org\/10.1146\/annurev-genom-090711-163729","DOI":"10.1146\/annurev-genom-090711-163729"},{"key":"ref10","doi-asserted-by":"publisher","unstructured":"[11] Deshpande AS, Goudy SL. Cellular and molecular mechanisms of cleft palate development. Laryngoscope Investig Otolaryngol, 2018, 4(1):160-164. https:\/\/doi.org\/10.1002\/lio2.214","DOI":"10.1002\/lio2.214"},{"key":"ref11","doi-asserted-by":"publisher","unstructured":"[12] Hammond NL, Dixon J, Dixon MJ. Periderm: life-cycle and function during orofacial and epidermal development. Semin Cell Dev Biol, 2019, 91:75-83. https:\/\/doi.org\/10.1016\/j.semcdb.2017.08.021","DOI":"10.1016\/j.semcdb.2017.08.021"},{"key":"ref12","doi-asserted-by":"publisher","unstructured":"[13] Ji Y, Garland MA, Sun B, Zhang S, Reynolds K, McMahon M, Rajakumar R, Islam MS, Liu Y, Chen Y, Zhou CJ. Cellular and developmental basis of orofacial clefts. Birth Defects Res, 2020, 112(19):1558-1587. https:\/\/doi.org\/10.1002\/bdr2.1768","DOI":"10.1002\/bdr2.1768"},{"key":"ref13","doi-asserted-by":"publisher","unstructured":"[14] Rahimov F, Jugessur A, Murray JC. Genetics of nonsyndromic orofacial clefts. Cleft Palate Craniofac J, 2012, 49(1):73-91. https:\/\/doi.org\/10.1597\/10-178","DOI":"10.1597\/10-178"},{"key":"ref14","doi-asserted-by":"publisher","unstructured":"[15] Antiguas A, Paul BJ, Dunnwald M. To stick or not to stick: adhesions in orofacial clefts. Biology (Basel), 2022, 11(2):153. https:\/\/doi.org\/10.3390\/biology11020153","DOI":"10.3390\/biology11020153"},{"key":"ref15","doi-asserted-by":"publisher","unstructured":"[16] Bush JO, Jiang R. Palatogenesis: morphogenetic and molecular mechanisms of secondary palate development. Development, 2012, 139(2):231-243. https:\/\/doi.org\/10.1242\/dev.067082","DOI":"10.1242\/dev.067082"},{"key":"ref16","doi-asserted-by":"publisher","unstructured":"[17] Gritli-Linde A. Molecular control of secondary palate development. Dev Biol, 2007, 301(2):309-326. https:\/\/doi.org\/10.1016\/j.ydbio.2006.07.042","DOI":"10.1016\/j.ydbio.2006.07.042"},{"key":"ref17","doi-asserted-by":"publisher","unstructured":"[18] Lan Y, Xu J, Jiang R. Cellular and molecular mechanisms of palatogenesis. Curr Top Dev Biol, 2015, 115:59-84. https:\/\/doi.org\/10.1016\/bs.ctdb.2015.07.002","DOI":"10.1016\/bs.ctdb.2015.07.002"},{"key":"ref18","doi-asserted-by":"publisher","unstructured":"[19] Lane J, Kaartinen V. Signaling networks in palate development. Wiley Interdiscip Rev Syst Biol Med, 2014, 6(3):271-278. https:\/\/doi.org\/10.1002\/wsbm.1265","DOI":"10.1002\/wsbm.1265"},{"key":"ref19","doi-asserted-by":"publisher","unstructured":"[20] Li C, Lan Y, Jiang R. Molecular and cellular mechanisms of palate development. J Dent Res, 2017, 96(11):1184-1191. https:\/\/doi.org\/10.1177\/0022034517703580","DOI":"10.1177\/0022034517703580"},{"key":"ref20","doi-asserted-by":"publisher","unstructured":"[21] Won HJ, Kim JW, Won HS, Shin JO. Gene regulatory networks and signaling pathways in palatogenesis and cleft palate: a comprehensive review. Cells, 2023, 12(15):1954. https:\/\/doi.org\/10.3390\/cells12151954","DOI":"10.3390\/cells12151954"},{"key":"ref21","doi-asserted-by":"publisher","unstructured":"[22] Twigg SRF, Wilkie AOM. New insights into craniofacial malformations. Hum Mol Genet, 2015, 24(R1):R50-R59. https:\/\/doi.org\/10.1093\/hmg\/ddv228","DOI":"10.1093\/hmg\/ddv228"},{"key":"ref22","doi-asserted-by":"publisher","unstructured":"[23] Ferretti E, Li B, Zewdu R, Wells V, Hebert JM, Karner C, Anderson MJ, Williams T, Dixon J, Dixon MJ, Depew MJ, Selleri L. A conserved Pbx-Wnt-p63-Irf6 regulatory module controls face morphogenesis by promoting epithelial apoptosis. Dev Cell, 2011, 21(4):627-641. https:\/\/doi.org\/10.1016\/j.devcel.2011.08.005","DOI":"10.1016\/j.devcel.2011.08.005"},{"key":"ref23","doi-asserted-by":"publisher","unstructured":"[24] Losa M, Risolino M, Li B, Hart J, Quintana L, Grishina I, Yang H, Choi IF, Lewicki P, Khan S, Aho R, Feenstra J, Vincent CT, Brown AMC, Ferretti E, Williams T, Selleri L. Face morphogenesis is promoted by Pbx-dependent EMT via regulation of Snail1 during frontonasal prominence fusion. Development, 2018, 145(5):dev157628. https:\/\/doi.org\/10.1242\/dev.157628","DOI":"10.1242\/dev.157628"},{"key":"ref24","doi-asserted-by":"publisher","unstructured":"[25] Xavier GM, Seppala M, Barrell W, Birjandi A A, Geoghegan F, Cobourne MT. Hedgehog receptor function during craniofacial development. Dev Biol, 2016, 415(2):198-215. https:\/\/doi.org\/10.1016\/j.ydbio.2016.02.009","DOI":"10.1016\/j.ydbio.2016.02.009"},{"key":"ref25","doi-asserted-by":"publisher","unstructured":"[26] Abramyan J, Richman JM. Recent insights into the morphological diversity in the amniote primary and secondary palates. Dev Dyn, 2015, 244(12):1457-1468. https:\/\/doi.org\/10.1002\/dvdy.24338","DOI":"10.1002\/dvdy.24338"},{"key":"ref26","doi-asserted-by":"publisher","unstructured":"[27] Jiang R, Bush JO, Lidral AC. Development of the upper lip: morphogenetic and molecular mechanisms. Dev Dyn, 2006, 235(5):1152-1166. https:\/\/doi.org\/10.1002\/dvdy.20646","DOI":"10.1002\/dvdy.20646"},{"key":"ref27","unstructured":"[28] Moxham BJ. The development of the palate - a brief review. Eur J Anat, 2003, 7(S1):53-74."},{"key":"ref28","doi-asserted-by":"publisher","unstructured":"[29] Lan Y, Jiang R. Mouse models in palate development and orofacial cleft research: understanding the crucial role and regulation of epithelial integrity in facial and palate morphogenesis. Curr Topics Dev Biol, 2022, 148:13-50. https:\/\/doi.org\/10.1016\/bs.ctdb.2021.12.003","DOI":"10.1016\/bs.ctdb.2021.12.003"},{"key":"ref29","doi-asserted-by":"publisher","unstructured":"[30] Hammond NL, Dixon MJ. Revisiting the embryogenesis of lip and palate development. Oral Dis, 2022, 28(5):1306-1326. https:\/\/doi.org\/10.1111\/odi.14174","DOI":"10.1111\/odi.14174"},{"key":"ref30","doi-asserted-by":"publisher","unstructured":"[31] Fraser FC, Pashayan H. Relation of face shape to susceptibility to congenital cleft lip. A preliminary report. J Med Genet, 1970, 7(2):112-117. https:\/\/doi.org\/10.1136\/jmg.7.2.112","DOI":"10.1136\/jmg.7.2.112"},{"key":"ref31","doi-asserted-by":"publisher","unstructured":"[32] Millicovsky G, Johnston MC. Active role of embryonic facial epithelium: new evidence of cellular events in morphogenesis. J Embryol Exp Morphol, 1981, 63:53-66.","DOI":"10.1242\/dev.63.1.53"},{"key":"ref32","doi-asserted-by":"publisher","unstructured":"[33] Poswillo D. The aetiology and pathogenesis of craniofacial deformity. Development, 1988, 103(Suppl):207-212. https:\/\/doi.org\/10.1242\/dev.103.Supplement.207","DOI":"10.1242\/dev.103.Supplement.207"},{"key":"ref33","doi-asserted-by":"publisher","unstructured":"[34] Sperber GH. Formation of the primary palate. In: Wyszynski DF (ed). Cleft lip and palate: from origin to treatment. Oxford University Press, Oxford, UK, 2002, 5-13. https:\/\/doi.org\/10.1093\/oso\/9780195139068.001.0001","DOI":"10.1093\/oso\/9780195139068.001.0001"},{"key":"ref34","doi-asserted-by":"publisher","unstructured":"[35] Li H, Jones KL, Hooper JE, Williams T. The molecular anatomy of mammalian upper lip and primary palate fusion at single cell resolution. Development, 2019, 146(12):dev174888. https:\/\/doi.org\/10.1242\/dev.174888","DOI":"10.1242\/dev.174888"},{"key":"ref35","doi-asserted-by":"publisher","unstructured":"[36] Sun D, Baur S, Hay ED. Epithelial-mesenchymal transformation is the mechanism for fusion of the craniofacial primordia involved in morphogenesis of the chicken lip. Dev Biol, 2000, 228(2):337-349. https:\/\/doi.org\/10.1006\/dbio.2000.9946","DOI":"10.1006\/dbio.2000.9946"},{"key":"ref36","doi-asserted-by":"publisher","unstructured":"[37] Hu L, Liu J, Li Z, Ozturk F, Gurumurthy C, Romano RA, Sinha S, Nawshad A. TGF\u03b23 regulates periderm removal through \u0394Np63 in the developing palate. J Cell Physiol, 2015, 230(6):1212-1225. https:\/\/doi.org\/10.1002\/jcp.24856","DOI":"10.1002\/jcp.24856"},{"key":"ref37","doi-asserted-by":"publisher","unstructured":"[38] Richardson R, Mitchell K, Hammond NL, Mollo MR, Kouwenhoven EN, Wyatt ND, Donaldson IJ, Zeef L, Burgis T, Blance R, van Heeringen SJ, Stunnenberg HG, Zhou H, Missero C, Romano RA, Sinha S, Dixon MJ, Dixon J. p63 exerts spatio-temporal control of palatal epithelial cell fate to prevent cleft palate. PLoS Genet, 2017, 13(6):e1006828. https:\/\/doi.org\/10.1371\/journal.pgen.1006828","DOI":"10.1371\/journal.pgen.1006828"},{"issue":"3","key":"ref38","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1387\/ijdb.10853831","article-title":"Bulging medial edge epithelial cells and palatal fusion","volume":"44","author":"Mart\u00ednez-Alvarez","year":"2000","unstructured":"[39] Mart\u00ednez-Alvarez C, Bonelli R, Tudela C, Gato A, Mena J, O'Kane S, Ferguson MW. Bulging medial edge epithelial cells and palatal fusion. Int J Dev Biol, 2000, 44(3):331-335.","journal-title":"Int J Dev Biol"},{"key":"ref39","doi-asserted-by":"publisher","unstructured":"[40] Mart\u00ednez-Alvarez C, Tudela C, P\u00e9rez-Miguelsanz J, O'Kane S, Puerta J, Ferguson MWJ. Medial edge epithelial cell fate during palatal fusion. Dev Biol, 2000, 220(2):343-357. https:\/\/doi.org\/10.1006\/dbio.2000.9644","DOI":"10.1006\/dbio.2000.9644"},{"key":"ref40","doi-asserted-by":"publisher","unstructured":"[41] Jin YR, Han XH, Taketo MM, Yoon JK. Wnt9b-dependent FGF signaling is crucial for outgrowth of the nasal and maxillary processes during upper jaw and lip development. Development, 2012, 139(10):1821-1830. https:\/\/doi.org\/10.1242\/dev.075796","DOI":"10.1242\/dev.075796"},{"key":"ref41","doi-asserted-by":"publisher","unstructured":"[42] Song L, Li Y, Wang K, Wang YZ, Molotkov A, Gao L, Zhao T, Yamagami T, Wang Y, Gan Q, Pleasure DE, Zhou CJ. Lrp6-mediated canonical Wnt signaling is required for lip formation and fusion. Development, 2009, 136(18):3161-3171. https:\/\/doi.org\/10.1242\/dev.037440","DOI":"10.1242\/dev.037440"},{"key":"ref42","doi-asserted-by":"publisher","unstructured":"[43] Kurosaka H, Iulianella A, Williams T, Trainor PA. Disrupting hedgehog and WNT signaling interactions promotes cleft lip pathogenesis. J Clin Invest, 2014, 124(4):1660-1671. https:\/\/doi.org\/10.1172\/JCI72688","DOI":"10.1172\/JCI72688"},{"key":"ref43","doi-asserted-by":"publisher","unstructured":"[44] Cuervo R, Covarrubias L. Death is the major fate of medial edge epithelial cells and the cause of basal lamina degradation during palatogenesis. Development, 2004, 131(1):15-24. https:\/\/doi.org\/10.1242\/dev.00907","DOI":"10.1242\/dev.00907"},{"key":"ref44","doi-asserted-by":"publisher","unstructured":"[45] Reynolds K, Kumari P, Sepulveda Rincon L, Gu R, Ji Y, Kumar S, Zhou CJ. Wnt signaling in orofacial clefts: crosstalk, pathogenesis and models. Dis Model Mech, 2019, 12(2):dmm037051. https:\/\/doi.org\/10.1242\/dmm.037051","DOI":"10.1242\/dmm.037051"},{"key":"ref45","doi-asserted-by":"publisher","unstructured":"[46] Lan Y, Jiang R. Sonic hedgehog signaling regulates reciprocal epithelial-mesenchymal interactions controlling palatal outgrowth. Development, 2009, 136(8):1387-1396. https:\/\/doi.org\/10.1242\/dev.028167","DOI":"10.1242\/dev.028167"},{"key":"ref46","doi-asserted-by":"publisher","unstructured":"[47] Xu J, Liu H, Lan Y, Aronow BJ, Kalinichenko VV, Jiang R. A Shh-Foxf-Fgf18-Shh molecular circuit regulating palate development. PLoS Genet, 2016, 12(1):e1005769. https:\/\/doi.org\/10.1371\/journal.pgen.1005769","DOI":"10.1371\/journal.pgen.1005769"},{"key":"ref47","doi-asserted-by":"publisher","unstructured":"[48] Zhang Z, Song Y, Zhao X, Zhang X, Fermin C, Chen Y. 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, 2002, 129(17):4135-4146. https:\/\/doi.org\/10.1242\/dev.129.17.4135","DOI":"10.1242\/dev.129.17.4135"},{"key":"ref48","doi-asserted-by":"publisher","unstructured":"[49] He F, Xiong W, Yu X, Espinoza-Lewis R, Liu C, Gu S, Nishita M, Suzuki K, Yamada G, Minami Y, Chen Y. Wnt5a regulates directional cell migration and cell proliferation via Ror2-mediated noncanonical pathway in mammalian palate development. Development, 2008, 135(23):3871-3879. https:\/\/doi.org\/10.1242\/dev.025767","DOI":"10.1242\/dev.025767"},{"key":"ref49","doi-asserted-by":"publisher","unstructured":"[50] Goering JP, Moedritzer M, Stetsiv M, Isai DG, Hufft-Martinez BM, Tran AJ, Umar Z, Rickabaugh MK, Keselman P, Chauhan M, Tran PV, Brooks WM, Fischer KJ, Czirok A, Saadi I. Novel insights into palatal shelf elevation dynamics in normal mouse embryos. Front Cell Dev Biol, 2025, 13:1532448. https:\/\/doi.org\/10.3389\/fcell.2025.1532448","DOI":"10.3389\/fcell.2025.1532448"},{"key":"ref50","doi-asserted-by":"publisher","unstructured":"[51] Fitchett JE, Hay ED. Medial edge epithelium transforms to mesenchyme after embryonic palatal shelves fuse. Dev Biol, 1989, 131(2):455-474. https:\/\/doi.org\/10.1016\/s0012-1606(89)80017-x","DOI":"10.1016\/S0012-1606(89)80017-X"},{"key":"ref51","doi-asserted-by":"publisher","unstructured":"[52] Taya Y, O'Kane S, Ferguson MW. Pathogenesis of cleft palate in TGF-\u03b23 knockout mice. Development, 1999, 126(17):3869-3879. https:\/\/doi.org\/10.1242\/dev.126.17.3869","DOI":"10.1242\/dev.126.17.3869"},{"key":"ref52","doi-asserted-by":"publisher","unstructured":"[53] Carette MJ, Ferguson MW. The fate of medial edge epithelial cells during palatal fusion in vitro: an analysis by Dil labelling and confocal microscopy. Development, 1992, 114(2):379-388. https:\/\/doi.org\/10.1242\/dev.114.2.379","DOI":"10.1242\/dev.114.2.379"},{"key":"ref53","doi-asserted-by":"publisher","unstructured":"[54] Kaartinen V, Cui XM, Heisterkamp N, Groffen J, Shuler CF. Transforming growth factor\u2010\u03b23 regulates transdifferentiation of medial edge epithelium during palatal fusion and associated degradation of the basement membrane. Dev Dyn, 1997, 209(3):255-260. https:\/\/doi.org\/10.1002\/(sici)1097-0177(199707)209:3%3C255::aid-aja1%3E3.0.co;2-h","DOI":"10.1002\/(SICI)1097-0177(199707)209:3<255::AID-AJA1>3.3.CO;2-N"},{"key":"ref54","doi-asserted-by":"publisher","unstructured":"[55] Logan SM, Ruest LB, Benson MD, Svoboda KKH. Extracellular matrix in secondary palate development. Anat Rec (Hoboken), 2020, 303(6):1543-1556. https:\/\/doi.org\/10.1002\/ar.24263","DOI":"10.1002\/ar.24263"},{"key":"ref55","doi-asserted-by":"publisher","unstructured":"[56] Ke CY, Xiao WL, Chen CM, Lo LJ, Wong FH. IRF6 is the mediator of TGF\u03b23 during regulation of the epithelial mesenchymal transition and palatal fusion. Sci Rep, 2015, 5:12791. https:\/\/doi.org\/10.1038\/srep12791","DOI":"10.1038\/srep12791"},{"key":"ref56","doi-asserted-by":"publisher","unstructured":"[57] Nakajima A, Shuler CF, Gulka AOD, Hanai JI. TGF-\u03b2 signaling and the epithelial-mesenchymal transition during palatal fusion. Int J Mol Sci, 2018, 19(11):3638. https:\/\/doi.org\/10.3390\/ijms1911363","DOI":"10.3390\/ijms19113638"},{"key":"ref57","doi-asserted-by":"publisher","unstructured":"[58] Kim S, Lewis AE, Singh V, Ma X, Adelstein R, Bush JO. Convergence and extrusion are required for normal fusion of the mammalian secondary palate. PLoS Biol, 2015, 13(4):e1002122. https:\/\/doi.org\/10.1371\/journal.pbio.1002122","DOI":"10.1371\/journal.pbio.1002122"},{"key":"ref58","doi-asserted-by":"publisher","unstructured":"[59] Frebourg T, Oliveira C, Hochain P, Karam R, Manouvrier S, Graziadio C, Vekemans M, Hartmann A, Baert-Desurmont S, Alexandre C, Lejeune Dumoulin S, Marroni C, Martin C, Castedo S, Lovett M, Winston J, Machado JC, Atti\u00e9 T, Jabs EW, Cai J, Pellerin P, Triboulet JP, Scotte M, Le Pessot F, Hedouin A, Carneiro F, Blayau M, Seruca R. Cleft lip\/palate and CDH1\/E-cadherin mutations in families with hereditary diffuse gastric cancer. J Med Genet, 2006, 43(2):138-142. https:\/\/doi.org\/10.1136\/jmg.2005.031385","DOI":"10.1136\/jmg.2005.031385"},{"key":"ref59","doi-asserted-by":"publisher","unstructured":"[60] He F, Xiong W, Wang Y, Li L, Liu C, Yamagami T, Taketo MM, Zhou C, Chen Y. Epithelial Wnt\/\u03b2-catenin signaling regulates palatal shelf fusion through regulation of Tgf\u03b23 expression. Dev Biol, 2011, 350(2):511-519. https:\/\/doi.org\/10.1016\/j.ydbio.2010.12.021","DOI":"10.1016\/j.ydbio.2010.12.021"},{"key":"ref60","doi-asserted-by":"publisher","unstructured":"[61] Teng T, Teng CS, Kaartinen V, Bush JO. A unique form of collective epithelial migration is crucial for tissue fusion in the secondary palate and can overcome loss of epithelial apoptosis. Development, 2022, 149(10):dev200181. https:\/\/doi.org\/10.1242\/dev.200181","DOI":"10.1242\/dev.200181"},{"key":"ref61","doi-asserted-by":"publisher","unstructured":"[62] Guarino M, Micheli P, Pallotti F, Giordano F. Pathological relevance of epithelial and mesenchymal phenotype plasticity. Pathol Res Pract, 1999, 195(6):379-389. https:\/\/doi.org\/10.1016\/S0344-0338(99)80011-9","DOI":"10.1016\/S0344-0338(99)80011-9"},{"key":"ref62","doi-asserted-by":"publisher","unstructured":"[63] Guarino M, Giordano F, Pallotti F, Polizzotti G, Tricomi P, Cristofori E. Malignant mixed m\u00fcllerian tumor of the uterus. Features favoring its origin from a common cell clone and an epithelial-to-mesenchymal transformation mechanism of histogenesis. Tumori, 1998, 84(3):391-397. https:\/\/doi.org\/10.1177\/030089169808400316","DOI":"10.1177\/030089169808400316"},{"key":"ref63","doi-asserted-by":"publisher","unstructured":"[64] Guarino M, Giordano F. Experimental induction of epithelial-mesenchymal interconversions. Exp Toxicol Pathol, 1995, 47(5):325-334. https:\/\/doi.org\/10.1016\/S0940-2993(11)80342-8","DOI":"10.1016\/S0940-2993(11)80342-8"},{"key":"ref64","doi-asserted-by":"publisher","unstructured":"[65] Ke FFS, Vanyai HK, Cowan AD, Delbridge ARD, Whitehead L, Grabow S, Czabotar PE, Voss AK, Strasser A. Embryogenesis and adult life in the absence of intrinsic apoptosis effectors BAX, BAK, and BOK. Cell, 2018, 173(5):1217-1230.e17. https:\/\/doi.org\/10.1016\/j.cell.2018.04.036","DOI":"10.1016\/j.cell.2018.04.036"},{"key":"ref65","doi-asserted-by":"publisher","unstructured":"[66] Teng X, Toyama Y. Apoptotic force: active mechanical function of cell death during morphogenesis. Dev Growth Differ, 2011, 53(2):269-276. https:\/\/doi.org\/10.1111\/j.1440-169X.2011.01251.x","DOI":"10.1111\/j.1440-169X.2011.01251.x"},{"key":"ref66","doi-asserted-by":"publisher","unstructured":"[67] Reynolds K, Zhang S, Sun B, Garland MA, Ji Y, Zhou CJ. Genetics and signaling mechanisms of orofacial clefts. Birth Defects Res, 2020, 112(19):1588-1634. https:\/\/doi.org\/10.1002\/bdr2.1754\"","DOI":"10.1002\/bdr2.1754"}],"container-title":["Romanian Journal of Morphology and Embryology"],"original-title":[],"link":[{"URL":"https:\/\/rjme.ro\/RJME\/resources\/files\/670126053062.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T22:59:09Z","timestamp":1784329149000},"score":1,"resource":{"primary":{"URL":"https:\/\/rjme.ro\/archive\/67\/1\/5\/"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,2]]},"references-count":67,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,7,12]]},"published-print":{"date-parts":[[2026,7,12]]}},"URL":"https:\/\/doi.org\/10.47162\/rjme.67.1.05","relation":{},"ISSN":["1220-0522","2066-8279"],"issn-type":[{"value":"1220-0522","type":"print"},{"value":"2066-8279","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,2]]}}}