Talk:Palate Development

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Cite this page: Hill, M.A. (2019, October 17) Embryology Palate Development. Retrieved from



TGF-β Signaling and the Epithelial-Mesenchymal Transition during Palatal Fusion

Int J Mol Sci. 2018 Nov 19;19(11). pii: E3638. doi: 10.3390/ijms19113638.

Nakajima A1, F Shuler C2, Gulka AOD3, Hanai JI4,5. Author information Abstract Signaling by transforming growth factor (TGF)-β plays an important role in development, including in palatogenesis. The dynamic morphological process of palatal fusion occurs to achieve separation of the nasal and oral cavities. Critically and specifically important in palatal fusion are the medial edge epithelial (MEE) cells, which are initially present at the palatal midline seam and over the course of the palate fusion process are lost from the seam, due to cell migration, epithelial-mesenchymal transition (EMT), and/or programed cell death. In order to define the role of TGF-β signaling during this process, several approaches have been utilized, including a small interfering RNA (siRNA) strategy targeting TGF-β receptors in an organ culture context, the use of genetically engineered mice, such as Wnt1-cre/R26R double transgenic mice, and a cell fate tracing through utilization of cell lineage markers. These approaches have permitted investigators to distinguish some specific traits of well-defined cell populations throughout the palatogenic events. In this paper, we summarize the current understanding on the role of TGF-β signaling, and specifically its association with MEE cell fate during palatal fusion. TGF-β is highly regulated both temporally and spatially, with TGF-β3 and Smad2 being the preferentially expressed signaling molecules in the critical cells of the fusion processes. Interestingly, the accessory receptor, TGF-β type 3 receptor, is also critical for palatal fusion, with evidence for its significance provided by Cre-lox systems and siRNA approaches. This suggests the high demand of ligand for this fine-tuned signaling process. We discuss the new insights in the fate of MEE cells in the midline epithelial seam (MES) during the palate fusion process, with a particular focus on the role of TGF-β signaling. KEYWORDS: TGF-β signaling; cleft palate; collective epithelial migration; crowding; epithelial-mesenchymal transition (EMT); midline epithelial seam (MES); palatal fusion; palatal medial edge epithelial (MEE) cells PMID: 30463190 DOI: 10.3390/ijms19113638

Development of Hard and Soft Palate During the Fetal Period and Hard Palate Asymmetry

J Craniofac Surg. 2018 Nov;29(8):2358-2362. doi: 10.1097/SCS.0000000000005016.

Dursun A1, Öztürk K, Albay S. Author information Abstract In the present study, it was aimed to perform the morphometric analysis of the hard and soft palate in fetal cadavers and evaluate hard palate asymmetry during the fetal development. The development of the palate was investigated in 40 (21 males, 19 females) fetal materials aged between the 17th and 40th gestational week. In this study, distances between the incisive papilla-staurion (Ip-Sr), staurion-posterior nasal spine (Sr-Pns), incisive papilla-greater palatine foramen (Ip-Gpf) on the right and left sides, Sr-Gpf, and Pns-Gpf were measured. In cases with asymmetry, the ratio of asymmetry was determined in percentage using the asymmetry index. Moreover, angular values between Ip-Sr-Gpf and Ip-Pns-Gpf on the right and left sides were measured, and the right and left side values were compared with each other. The hard and soft palate lengths were measured on the planum medianum. Upon comparing the measured parameters between males and females, the mean values of male fetuses were higher in all parameters, but a significant difference was found only in the Sr-Pns distance among these parameters. Upon comparing the angular data and asymmetry index data on the hard palate between the trimester groups, a significant difference was found only in the Ip-Sr-Gpf (left) parameter. The mean ratio of the hard palate to the soft palate was found as 1.90. It is believed that the obtained data will contribute to studies to be conducted in fields such as plastic surgery, maxillofacial surgery, intrauterine surgery, fetopathology, embryology, anatomy, and obstetrics. PMID: 30320695 DOI: 10.1097/SCS.0000000000005016


Dev Dyn. 2016 Feb;245(2):123-31. doi: 10.1002/dvdy.24364. Epub 2015 Dec 1. Three-dimensional imaging of palatal muscles in the human embryo and fetus: Development of levator veli palatini and clinical importance of the lesser palatine nerve. Kishimoto H1,2, Yamada S2,3, Kanahashi T3, Yoneyama A4, Imai H5, Matsuda T5, Takeda T4, Kawai K1, Suzuki S1. Author information Abstract BACKGROUND: After palatoplasty, incomplete velopharyngeal closure in speech articulation sometimes persists, despite restoration of deglutition function. The levator veli palatini (LVP) is believed to be significantly involved with velopharyngeal function in articulation; however, the development and innervation of LVP remain obscure. The development of LVP in human embryos and fetuses has not been systematically analyzed using the Carnegie stage (CS) to standardize documentation of development. RESULTS: The anlage of LVP starts to develop at CS 21 beneath the aperture of the auditory tube (AT) to the pharynx. At CS 23, LVP runs along AT over its full length, as evidenced by three-dimensional image reconstruction. In the fetal stage, the lesser palatine nerve (LPN) is in contact with LVP. CONCLUSIONS: The positional relationship between LVP and AT three-dimensionally, suggesting that LVP might be derived from the second branchial arch. Based on histological evidence, we hypothesize that motor components from the facial nerve may run along LPN, believed to be purely sensory. The multiple innervation of LVP by LPN and pharyngeal plexus may explain the postpalatoplasty discrepancy between the partial impairment in articulation vs. the functional restoration of deglutition. That is, the contribution of LPN is greater in articulation than in deglutition. © 2015 Wiley Periodicals, Inc. KEYWORDS: Kyoto collection; human embryo; human fetus; lesser palatine nerve; levator veli palatini muscle; palatoplasty; phase-contrast imaging PMID: 26509917


Cellular and Molecular Mechanisms of Palatogenesis

Curr Top Dev Biol. 2015;115:59-84. doi: 10.1016/bs.ctdb.2015.07.002. Epub 2015 Oct 1.

Lan Y1, Xu J2, Jiang R3.


Palatogenesis involves the initiation, growth, morphogenesis, and fusion of the primary and secondary palatal shelves from initially separate facial prominences during embryogenesis to form the intact palate separating the oral cavity from the nostrils. The palatal shelves consist mainly of cranial neural crest-derived mesenchymal cells covered by a simple embryonic epithelium. The growth and patterning of the palatal shelves are controlled by reciprocal epithelial-mesenchymal interactions regulated by multiple signaling pathways and transcription factors. During palatal shelf outgrowth, the embryonic epithelium develops a "teflon" coat consisting of a single, continuous layer of periderm cells that prevents the facial prominences and palatal shelves from forming aberrant interepithelial adhesions. Palatal fusion involves not only spatiotemporally regulated disruption of the periderm but also dynamic cellular and molecular processes that result in adhesion and intercalation of the palatal medial edge epithelia to form an intershelf epithelial seam, and subsequent dissolution of the epithelial seam to form the intact roof of the oral cavity. The complexity of regulation of these morphogenetic processes is reflected by the common occurrence of cleft palate in humans. This review will summarize major recent advances and discuss major remaining gaps in the understanding of cellular and molecular mechanisms controlling palatogenesis. © 2015 Elsevier Inc. All rights reserved. KEYWORDS: Cleft palate; Fusion; Morphogenesis; Mouse; Palate development; Periderm; Signaling PMID 26589921

Global Birth Prevalence of Orofacial Clefts: A Systematic Review

J Med Assoc Thai. 2015 Aug;98 Suppl 7:S11-21.

Panamonta V, Pradubwong S, Panamonta M, Chowchuen B.


BACKGROUND: A birth prevalence of orofacial clefts (OFCs) worldwide has been documented to vary. However a systematic assessment is lacking. OBJECTIVE: To assess the evidence in the literature for the birth prevalence of OFCs. MATERIAL AND METHOD: A systematic literature search was conducted using electronic databases through PubMed between 1950 and June 2015 using key words and search terms of cleft lip palate OR orofacial cleft AND prevalence. RESULTS: There were 45,193 patients with OFCs found in a study population of 30,665,615 live births. According to continents, the OFC birth prevalence (95% confidence interval) from Asia, North America, Europe, Oceania, South America, and Africa were 1.57 (1.54-1.60), 1.56 (1.53-1.59), 1.55 (1.52-1.58), 1.33 (1.30-1.36), 0.99 (0.96-1.02), and 0.57 (0.54-0.60) per 1,000 live births, respectively. The American Indians had the highest prevalence rates of 2.62 per 1,000 live births, followed by the Japanese, the Chinese, and the Whites of 1.73, 1.56, and 1.55 per 1,000 live births, respectively. The Blacks had the lowest rate of 0.58 per 1,000 live births. CONCLUSION: Observed differences may also be of ethnic origin, genetic, environmental factors, and methods of ascertainment. Further investigations are needed to manage this global health problem. PMID 26742364

Folic acid supplements and risk for oral clefts in the newborn: a population-based study

Br J Nutr. 2015 Sep 7:1-8. [Epub ahead of print]

Gildestad T1, Bjørge T1, Vollset SE1, Klungsøyr K1, Nilsen RM1, Haaland ØA1, Øyen N1.


Results from previous studies on maternal folic acid intake and infant oral clefts are inconclusive. The aim of the present study was to investigate the association between women's use of folic acid and/or multivitamin supplements and the risk for oral cleft in the newborn. We used data from the Medical Birth Registry of Norway based on all births in Norway from 1999 to 2013. A total of 528 220 women had 880 568 pregnancies, resulting in 896 674 live births and stillbirths, of which 1623 had oral clefts (isolated oral clefts, n 1311; non-isolated oral clefts, n 312). Altogether, 21·5 % of women were vitamin supplement users before pregnancy. The birth prevalence of oral clefts was 1·81/1000 live births and stillbirths. Relative risks (RR) were estimated with log-binomial regression. For pregnancies with maternal use of vitamins, the adjusted RR for clefts overall was 0·90 (95 % CI 0·79, 1·04). The adjusted RR for cleft palate only (n 586) was 0·84 (95 % CI 0·66, 1·06) and that for cleft lip with or without cleft palate (n 1037) was 0·94 (95 % CI 0·79, 1·13). Associations were stronger for cleft cases that occurred in combination with other malformations (adjusted RR 0·63; 95 % CI 0·45, 0·88), although vitamin supplements provided no protection against isolated clefts (adjusted RR 0·98; 95 % CI 0·84, 1·15). In conclusion, our study demonstrates no statistically significant association between vitamin use and isolated oral clefts. However, we found lower risk for oral clefts that occurred in combination with other malformations. KEYWORDS: CL(P) cleft lip with or without cleft palate; CPO cleft palate only; MBRN Medical Birth Registry of Norway; MoBa Norwegian Mother and Child Cohort Study; RR relative risk; Epidemiology; Folic acid; Health promotion; Multivitamins; Oral clefts; Reproduction

PMID 26343883

Classification of Cleft Lip/Palate: Then and Now

Cleft Palate Craniofac J. 2015 Sep 4. [Epub ahead of print]

Allori AC, Mulliken JB, Meara JG, Shusterman S, Marcus JR; CleftKit Collaboration.


Cleft lip and/or palate (CL/P) is phenotypically diverse, making classification difficult. This article explores the evolution of ideas regarding CL/P classification and includes the schemes described by Davis and Ritchie (1922), Brophy (1923), Veau (1931), Fogh-Andersen (1943), Kernahan and Stark (1958), Harkins et al. (1962), Broadbent et al. (1968), Spina (1973), and others. Based on these systems, a longhand structured form is proposed for describing CL/P in a way that is clear, comprehensive, and consistent. A complementary shorthand notation is also described to improve the utility and convenience of this structured form. KEYWORDS: CleftKit; classification; cleft lip; cleft palate; nomenclature; nosology; ontology; taxonomy; terminology

PMID 26339868


Signaling networks in palate development

Wiley Interdiscip Rev Syst Biol Med. 2014 May-Jun;6(3):271-8. doi: 10.1002/wsbm.1265. Epub 2014 Mar 18.

Lane J, Kaartinen V.


Palatogenesis, the formation of the palate, is a dynamic process regulated by a complex series of context-dependent morphogenetic signaling events. Many genes involved in palatogenesis have been discovered through the use of genetically manipulated mouse models as well as from human genetic studies, but the roles of these genes and their products in signaling networks regulating palatogenesis are still poorly known. In this review, we give a brief overview on palatogenesis and introduce key signaling cascades leading to formation of the intact palate. Moreover, we review conceptual differences between pathway biology and network biology and discuss how some of the recent technological advances in conjunction with mouse genetic models have contributed to our understanding of signaling networks regulating palate growth and fusion. For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors have declared no conflicts of interest for this article. © 2014 Wiley Periodicals, Inc.

PMID 24644145

Neural crest-specific deletion of Ldb1 leads to cleft secondary palate with impaired palatal shelf elevation

BMC Dev Biol. 2014 Jan 17;14(1):3. doi: 10.1186/1471-213X-14-3.

Almaidhan A, Cesario J, Landin Malt A, Zhao Y, Sharma N, Choi V, Jeong J1. Author information


BACKGROUND: LIM domain binding protein 1 (LDB1) is a transcriptional co-factor, which interacts with multiple transcription factors and other proteins containing LIM domains. Complete inactivation of Ldb1 in mice resulted in early embryonic lethality with severe patterning defects during gastrulation. Tissue-specific deletions using a conditional knockout allele revealed additional roles of Ldb1 in the development of the central nervous system, hematopoietic system, and limbs. The goal of the current study was to determine the importance of Ldb1 function during craniofacial development in mouse embryos. RESULTS: We generated tissue-specific Ldb1 mutants using Wnt1-Cre, which causes deletion of a floxed allele in the neural crest; neural crest-derived cells contribute to most of the mesenchyme of the developing face. All examined Wnt1-Cre;Ldb1fl/- mutants suffered from cleft secondary palate. Therefore, we performed a series of experiments to investigate how Ldb1 regulated palate development. First, we examined the expression of Ldb1 during normal development, and found that Ldb1 was expressed broadly in the palatal mesenchyme during early stages of palate development. Second, we compared the morphology of the developing palate in control and Ldb1 mutant embryos using sections. We found that the mutant palatal shelves had abnormally blunt appearance, and failed to elevate above the tongue at the posterior domain. An in vitro head culture experiment indicated that the elevation defect was not due to interference by the tongue. Finally, in the Ldb1 mutant palatal shelves, cell proliferation was abnormal in the anterior, and the expression of Wnt5a, Pax9 and Osr2, which regulate palatal shelf elevation, was also altered. CONCLUSIONS: The function of Ldb1 in the neural crest-derived palatal mesenchyme is essential for normal morphogenesis of the secondary palate. PMID 24433583


The etiology of cleft palate formation in BMP7-deficient mice

PLoS One. 2013;8(3):e59463. doi: 10.1371/journal.pone.0059463. Epub 2013 Mar 14.

Kouskoura T, Kozlova A, Alexiou M, Blumer S, Zouvelou V, Katsaros C, Chiquet M, Mitsiadis TA, Graf D. Author information


Palatogenesis is a complex process implying growth, elevation and fusion of the two lateral palatal shelves during embryogenesis. This process is tightly controlled by genetic and mechanistic cues that also coordinate the growth of other orofacial structures. Failure at any of these steps can result in cleft palate, which is a frequent craniofacial malformation in humans. To understand the etiology of cleft palate linked to the BMP signaling pathway, we studied palatogenesis in Bmp7-deficient mouse embryos. Bmp7 expression was found in several orofacial structures including the edges of the palatal shelves prior and during their fusion. Bmp7 deletion resulted in a general alteration of oral cavity morphology, unpaired palatal shelf elevation, delayed shelf approximation, and subsequent lack of fusion. Cell proliferation and expression of specific genes involved in palatogenesis were not altered in Bmp7-deficient embryos. Conditional ablation of Bmp7 with Keratin14-Cre or Wnt1-Cre revealed that neither epithelial nor neural crest-specific loss of Bmp7 alone could recapitulate the cleft palate phenotype. Palatal shelves from mutant embryos were able to fuse when cultured in vitro as isolated shelves in proximity, but not when cultured as whole upper jaw explants. Thus, deformations in the oral cavity of Bmp7-deficient embryos such as the shorter and wider mandible were not solely responsible for cleft palate formation. These findings indicate a requirement for Bmp7 for the coordination of both developmental and mechanistic aspects of palatogenesis.

PMID 23516636

Regulation of the Epithelial Adhesion Molecule CEACAM1 Is Important for Palate Formation

PLoS One. 2013 Apr 17;8(4):e61653. doi: 10.1371/journal.pone.0061653. Print 2013.

Mima J, Koshino A, Oka K, Uchida H, Hieda Y, Nohara K, Kogo M, Chai Y, Sakai T. Source Department of Oral-facial Disorders, Osaka University Graduate School of Dentistry, Suita, Osaka, Japan ; First Department of Oral and Maxillofacial Surgery, Osaka University Graduate School of Dentistry, Suita, Osaka, Japan. Abstract Cleft palate results from a mixture of genetic and environmental factors and occurs when the bilateral palatal shelves fail to fuse. The objective of this study was to search for new genes involved in mouse palate formation. Gene expression of murine embryonic palatal tissue was analyzed at various developmental stages before, during, and after palate fusion using GeneChip® microarrays. Ceacam1 was one of the highly up-regulated genes during palate formation, and this was confirmed by quantitative real-time PCR. Immunohistochemical staining showed that CEACAM1 was present in prefusion palatal epithelium and was degraded during fusion. To investigate the developmental role of CEACAM1, function-blocking antibody was added to embryonic mouse palate in organ culture. Palatal fusion was inhibited by this function-blocking antibody. To investigate the subsequent developmental role of CEACAM1, we characterized Ceacam1-deficient (Ceacam1 (-/-)) mice. Epithelial cells persisted abnormally at the midline of the embryonic palate even on day E16.0, and palatal fusion was delayed in Ceacam1 (-/-) mice. TGFβ3 expression, apoptosis, and cell proliferation in palatal epithelium were not affected in the palate of Ceacam1(-/-)mice. However, CEACAM1 expression was retained in the remaining MEE of TGFβ-deficient mice. These results suggest that CEACAM1 has roles in the initiation of palatal fusion via epithelial cell adhesion.

PMID 23613893



Tmem26 is dynamically expressed during palate and limb development but is not required for embryonic survival

PLoS One. 2011;6(9):e25228. Epub 2011 Sep 29. Town L, McGlinn E, Davidson TL, Browne CM, Chawengsaksophak K, Koopman P, Richman JM, Wicking C. Source Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.


The Tmem26 gene encodes a novel protein that we have previously shown to be regulated by hedgehog signalling in the mouse limb. We now report that Tmem26 expression is spatially and temporally restricted in other regions of the mouse embryo, most notably the facial primordia. In particular, Tmem26 expression in the mesenchyme of the maxillary and nasal prominences is coincident with fusion of the primary palate. In the secondary palate, Tmem26 is expressed in the palatal shelves during their growth and fusion but is downregulated once fusion is complete. Expression was also detected at the midline of the expanding mandible and at the tips of the eyelids as they migrate across the cornea. Given the spatio-temporally restricted expression of Tmem26, we sought to uncover a functional role in embryonic development through targeted gene inactivation in the mouse. However, ubiquitous inactivation of Tmem26 led to no overt phenotype in the resulting embryos or adult mice, suggesting that TMEM26 function is dispensable for embryonic survival.

PMID 21980401

Role of GSK-3β in the Osteogenic Differentiation of Palatal Mesenchyme

PLoS One. 2011;6(10):e25847. Epub 2011 Oct 14.

Nelson ER, Levi B, Sorkin M, James AW, Liu KJ, Quarto N, Longaker MT. Source Hagey Laboratory for Pediatric Regenerative Medicine, Plastic and Reconstructive Surgery Division, Department of Surgery, Stanford University School of Medicine, Stanford, California, United States of America.


INTRODUCTION: The function of Glycogen Synthase Kinases 3β (GSK-3β) has previously been shown to be necessary for normal secondary palate development. Using GSK-3ß null mouse embryos, we examine the potential coordinate roles of Wnt and Hedgehog signaling on palatal ossification.

METHODS: Palates were harvested from GSK-3β, embryonic days 15.0-18.5 (e15.0-e18.5), and e15.5 Indian Hedgehog (Ihh) null embryos, and their wild-type littermates. The phenotype of GSK-3β null embryos was analyzed with skeletal whole mount and pentachrome stains. Spatiotemporal regulation of osteogenic gene expression, in addition to Wnt and Hedgehog signaling activity, were examined in vivo on GSK-3β and Ihh +/+ and -/- e15.5 embryos using in situ hybridization and immunohistochemistry. To corroborate these results, expression of the same molecular targets were assessed by qRT-PCR of e15.5 palates, or e13.5 palate cultures treated with both Wnt and Hedgehog agonists and anatagonists.

RESULTS: GSK-3β null embryos displayed a 48 percent decrease (*p<0.05) in palatine bone formation compared to wild-type littermates. GSK-3β null embryos also exhibited decreased osteogenic gene expression that was associated with increased Wnt and decreased Hedgehog signaling. e13.5 palate culture studies demonstrated that Wnt signaling negatively regulates both osteogenic gene expression and Hedgehog signaling activity, while inhibition of Wnt signaling augments both osteogenic gene expression and Hedgehog signaling activity. In addition, no differences in Wnt signaling activity were noted in Ihh null embryos, suggesting that canonical Wnt may be upstream of Hedgehog in secondary palate development. Lastly, we found that GSK-3β -/- palate cultures were "rescued" with the Wnt inhibitor, Dkk-1.

CONCLUSIONS: Here, we identify a critical role for GSK-3β in palatogenesis through its direct regulation of canonical Wnt signaling. These findings shed light on critical developmental pathways involved in palatogenesis and may lead to novel molecular targets to prevent cleft palate formation.

PMID 22022457 [PubMed - in process] PMCID: PMC3194817

Histomorphological study of palatal shelf elevation during murine secondary palate formation

Dev Dyn. 2011 May 26. doi: 10.1002/dvdy.22670. Yu K, Ornitz DM. Source Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri.;


During mammalian secondary palate development, the palatal shelves undergo dramatic morphological changes to elevate from a vertical to a horizontal plane in the oral-nasal cavity. We found that E14.5 mouse embryos displayed marked variations in shelf morphology that represent various intermediate states of the elevation process. With these variations, we reconstructed the sequence of shelf morphological changes that take place during the elevation process and discovered distinct patterns in different regions along the anterior-posterior (AP) axis. Moreover, our study revealed that during the elevation process, shelf morphological changes are accompanied by tongue morphological changes, which also show distinct characteristics along the AP axis. We further discuss how to divide the palate along the AP axis based on morphological criteria. Our study provides a framework that recognizes variation in timing of palatal morphogenesis along the AP axis that will aid in the investigation of the mechanisms regulating palatal shelf elevation. Developmental Dynamics, 2011. © 2011 Wiley-Liss, Inc.

Copyright © 2011 Wiley-Liss, Inc.

  • In mammals, after bulging out bilaterally from the maxillary process, the palate shelves grow rapidly away from the maxilla along the side of the tongue.
  • Formation of the secondary palate requires the palatal shelves to undergo a process called shelf elevation or shelf reorientation
  • palate shelves move from lateral of the tongue to above the dorsum of the tongue and change their orientation in the oral-nasal cavity from vertical to horizontal.
  • the opposing horizontal shelves contact each other at the midline of the oral-nasal cavity
  • A midline epithelial seam (MES) is then formed by fusion of the medial edge epithelia (MEE) of the opposing palatal shelves.

Tongue changes during shelf elevation

  • displacement between the root of tongue and the extreme posterior end of the palate
  • tongue movement likely due to growth of the mandible (or Meckel's cartilage) in the lower jaw to which the root of the tongue is attached.
  • tongue expands laterally in the oral cavity
    • increases the dorsal width of the tongue along the medial-lateral (ML) axis
    • reduces tongue height along the dorsal-ventral (DV) axis.
  • tongue flattening - could result from tongue lateral expansion, which actually occurs throughout the entire palate

PMID: 21618642

Ephrin reverse signaling controls palate fusion via a PI3 kinase-dependent mechanism

Dev Dyn. 2011 Feb;240(2):357-64. doi: 10.1002/dvdy.22546.

San Miguel S, Serrano MJ, Sachar A, Henkemeyer M, Svoboda KK, Benson MD.

Department of Biomedical Sciences, Texas A&M Health Science Center Baylor College of Dentistry, Dallas, Texas. Abstract

Secondary palate fusion requires adhesion and epithelial-to-mesenchymal transition (EMT) of the epithelial layers on opposing palatal shelves. This EMT requires transforming growth factor β3 (TGFβ3), and its failure results in cleft palate. Ephrins, and their receptors, the Ephs, are responsible for migration, adhesion, and midline closure events throughout development. Ephrins can also act as signal-transducing receptors in these processes, with the Ephs serving as ligands (termed "reverse" signaling). We found that activation of ephrin reverse signaling in chicken palates induced fusion in the absence of TGFβ3, and that PI3K inhibition abrogated this effect. Further, blockage of reverse signaling inhibited TGFβ3-induced fusion in the chicken and natural fusion in the mouse. Thus, ephrin reverse signaling is necessary and sufficient to induce palate fusion independent of TGFβ3. These data describe both a novel role for ephrins in palate morphogenesis, and a previously unknown mechanism of ephrin signaling. Developmental Dynamics 240:357-364, 2011. © 2011 Wiley-Liss, Inc.

Copyright © 2011 Wiley-Liss, Inc.

PMID 21246652


The origin and early development of the nasal septum in human embryos

Ann Anat. 2010 Apr 20;192(2):82-5. Epub 2010 Jan 25. Steding G, Jian Y. Source Centre of Anatomy, Georg August University Goettingen, Kreuzbergring 36, 37075 Goettingen, Germany.


Based on scanning electron microscopic dissections of human embryos and fetuses of the sixth to the twelfth week (Carnegie stages 16-23 and early fetus), the origin of the nasal septum was studied. The findings show that the nasal septum does not grow downwards. It is derived from the tissue between the primary choanae: as such, its anlage is present from the very beginning. Its contact and fusion with the palatal shelves is made possible by the elevation of the palatal shelves from the vertical into the horizontal position, as the tongue descends. Copyright 2010 Elsevier GmbH. All rights reserved.

PMID 20149609

Incidence of cleft Lip and palate in the state of Andhra Pradesh, South India

Indian J Plast Surg. 2010 Jul;43(2):184-9.

Reddy SG, Reddy RR, Bronkhorst EM, Prasad R, Ettema AM, Sailer HF, Bergé SJ.

SourceGSR Institute of Craniofacial Surgery, Hyderabad, Andhra Pradesh, India.

Abstract OBJECTIVE:To assess the incidence of cleft lip and palate defects in the state of Andhra Pradesh, India.DESIGN SETTING:The study was conducted in 2001 in the state of Andhra Pradesh, India. The state has a population of 76 million. Three districts, Cuddapah, Medak and Krishna, were identified for this study owing to their diversity. They were urban, semi-urban and rural, respectively. Literacy rates and consanguinity of the parents was elicited and was compared to national averages to find correlations to cleft births. Type and side of cleft were recorded to compare with other studies around the world and other parts of India.RESULTS:The birth rate of clefts was found to be 1.09 for every 1000 live births. This study found that 65% of the children born with clefts were males. The distribution of the type of cleft showed 33% had CL, 64% had CLP, 2% had CP and 1% had rare craniofacial clefts. Unilateral cleft lips were found in 79% of the patients. Of the unilateral cleft lips 64% were left sided. There was a significant correlation of children with clefts being born to parents who shared a consanguineous relationship and those who were illiterate with the odds ratio between 5.25 and 7.21 for consanguinity and between 1.55 and 5.85 for illiteracy, respectively.CONCLUSION:The birth rate of clefts was found to be comparable with other Asian studies, but lower than found in other studies in Caucasian populations and higher than in African populations. The incidence was found to be similar to other studies done in other parts of India. The distribution over the various types of cleft was comparable to that found in other studies.

PMID 21217978

Epidemiologic factors causing cleft lip and palate and their regularities of occurrence in Estonia

Stomatologija. 2010;12(4):105-108.

Jagomagi T, Soots M, Saag M.

Department of Stomatology, Faculty of Medicine, University of Tartu, Kastani 16, Tartu 50410, Estonia.

Abstract OBJECTIVES. To study epidemiological factors causing development of cleft lip and palate and their occurrence regularities. MATERIALS AND METHODS. This study included 583 cleft lip and palate patients and the information for statistical analyses was gathered from Tartu University Hospital. RESULTS. 19% of the patients had a cleft lip (CL), 39% of the patients had a cleft palate (CP), and 42 % of the patients had a cleft lip and palate (CLP). The ratio for different cleft types CL: CLP: CP was 1:2:2. In unilateral CLP and CL cases, the left side was affected 2.2 times more frequently than the right side. Boys had a CLP nearly 2.1 times more often than girls. CP was more common for girls (60%) than for boys (40%). 30% of children had multiple malformations. 2.6% of children with clefts were born premature, half of which had accompanying developmental anomalies. The average birth weight for cleft child was ~ 3400 grams. 6.8% of children with clefts had a birth weight below 2.5 kg. In case of children with clefts, the mother's age exceeded 30 years in 1/4 of cases and father's age in 1/3 of cases. Both parents were older than 30 years in 66% of the cases. 1/5 of both parents were older than 30 years. 1/3 of mothers of children with clefts had suffered psychological stress, 1/5 of mothers had done hard physical work. 1/5 of mothers had an exposure to teratogenic toxic substances. 15% of them received medications during the first trimester of pregnancy. 15% of mothers had experienced hormonal disorders. CONCLUSIONS. As a result of the study we found a high occurrence rate of CP (CL: CLP: CP - 1:2:2), which is similar to the studies conducted in Finland and Sweden. The reasons for this ratio need further research.

PMID 21266834

A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4

Nat Genet. 2010 Jun;42(6):525-9. Epub 2010 May 2.

Beaty TH, Murray JC, Marazita ML, Munger RG, Ruczinski I, Hetmanski JB, Liang KY, Wu T, Murray T, Fallin MD, Redett RA, Raymond G, Schwender H, Jin SC, Cooper ME, Dunnwald M, Mansilla MA, Leslie E, Bullard S, Lidral AC, Moreno LM, Menezes R, Vieira AR, Petrin A, Wilcox AJ, Lie RT, Jabs EW, Wu-Chou YH, Chen PK, Wang H, Ye X, Huang S, Yeow V, Chong SS, Jee SH, Shi B, Christensen K, Melbye M, Doheny KF, Pugh EW, Ling H, Castilla EE, Czeizel AE, Ma L, Field LL, Brody L, Pangilinan F, Mills JL, Molloy AM, Kirke PN, Scott JM, Arcos-Burgos M, Scott AF.

Johns Hopkins University, School of Public Health, Baltimore, Maryland, USA. Erratum in:

Nat Genet. 2010 Aug;42(8):727. Scott, James M [corrected to Scott, John M]. Abstract Case-parent trios were used in a genome-wide association study of cleft lip with and without cleft palate. SNPs near two genes not previously associated with cleft lip with and without cleft palate (MAFB, most significant SNP rs13041247, with odds ratio (OR) per minor allele = 0.704, 95% CI 0.635-0.778, P = 1.44 x 10(-11); and ABCA4, most significant SNP rs560426, with OR = 1.432, 95% CI 1.292-1.587, P = 5.01 x 10(-12)) and two previously identified regions (at chromosome 8q24 and IRF6) attained genome-wide significance. Stratifying trios into European and Asian ancestry groups revealed differences in statistical significance, although estimated effect sizes remained similar. Replication studies from several populations showed confirming evidence, with families of European ancestry giving stronger evidence for markers in 8q24, whereas Asian families showed stronger evidence for association with MAFB and ABCA4. Expression studies support a role for MAFB in palatal development.

PMID 20436469

Matrix metalloproteinase-25 has a functional role in mouse secondary palate development and is a downstream target of TGF-β3

BMC Dev Biol. 2010 Sep 1;10:93.

Brown GD, Nazarali AJ.

Laboratory of Molecular Biology, College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5C9, Canada. Abstract BACKGROUND: Development of the secondary palate (SP) is a complex event and abnormalities during SP development can lead to cleft palate, one of the most common birth disorders. Matrix metalloproteinases (MMPs) are required for proper SP development, although a functional role for any one MMP in SP development remains unknown. MMP-25 may have a functional role in SP formation as genetic scans of the DNA of human cleft palate patients indicate a common mutation at a region upstream of the MMP-25 gene. We report on the gene expression profile of MMP-25 in the developing mouse SP and identify its functional role in mouse SP development.

RESULTS: MMP-25 mRNA and protein are found at all SP developmental stages in mice, with the highest expression at embryonic day (E) 13.5. Immunohistochemistry and in situ hybridization localize MMP-25 protein and mRNA, respectively, to the apical palate shelf epithelial cells and apical mesenchyme. MMP-25 knockdown with siRNA in palatal cultures results in a significant decrease in palate shelf fusion and persistence of the medial edge epithelium. MMP-25 mRNA and protein levels significantly decrease when cultured palate shelves are incubated in growth medium with 5 μg/mL of a TGF-β3-neutralizing antibody.

CONCLUSIONS: Our findings indicate: (i) MMP-25 gene expression is highest at E12.5 and E13.5, which corresponds with increasing palate shelf growth downward alongside the tongue; (ii) MMP-25 protein and mRNA expression predominantly localize in the apical epithelium of the palate shelves, but are also found in apical areas of the mesenchyme; (iii) knockdown of MMP-25 mRNA expression impairs palate shelf fusion and results in significant medial edge epithelium remaining in contacted areas; and (iv) bio-neutralization of TGF-β3 significantly decreases MMP-25 gene expression. These data suggest a functional role for MMP-25 in mouse SP development and are the first to identify a role for a single MMP in mouse SP development.

PMID: 20809987

Antenatal determinants of oro-facial clefts in Southern Nigeria

Afr Health Sci. 2010 Mar;10(1):31-9.

Omo-Aghoja VW, Omo-Aghoja LO, Ugboko VI, Obuekwe ON, Saheeb BD, Feyi-Waboso P, Onowhakpor A.

Department of Oral and Maxillofacial Surgery, Central Hospital, Sapele, Nigeria. Abstract OBJECTIVES: Cleft lip with or without cleft palate, is the most common serious congenital anomaly that affects the orofacial regions. The management and care of the cleft patient constitutes a substantial proportion of the workload of the Nigerian maxillofacial surgeon and allied specialties. Yet, there are no specific programmes targeted at this group. We believe that the findings of this study is capable of identifying useful interventions for designing programs that will lead to a reduction in the burden of orofacial cleft in Nigeria.

METHODS: It was a transverse cross-sectional study that was undertaken at the Maxillofacial Units of the University of Benin Teaching Hospital and the Central Hospital, Benin City respectively. The prevalence and antenatal determinants of cleft lip and palate were determined.

RESULTS: Cleft lip and palate were often encountered in clinical practice in Benin City with a prevalence of 1.35%. The results showed that orofacial clefts were commoner in females and that the combined unilateral cleft lip and palate was the commonest entity encountered amongst the cases. The following risk factors were associated with the risk of development of cleft lip and palate: Paternal age >40 years, maternal age >35 years, genetic/family history, low socio-economic status, alcohol consumption and indulgence in the intake of herbal medications in pregnancy.

CONCLUSION: Public health education programmes and advocacy activities geared towards raising awareness of the identified risk factors for the development of cleft lip and or cleft palate would go a long way to obviate the occurrence and reduce the burden.

PMID: 20811522


Internet-derived information on cleft lip and palate for families with affected children

Cleft Palate Craniofac J. 2009 Jan;46(1):75-80. Epub 2008 May 21. Antonarakis GS, Kiliaridis S. Source Department of Orthodontics, Dental School, University of Geneva, Switzerland.


OBJECTIVE: To investigate the nature and readability of cleft lip and palate-related family information on the Internet. MATERIALS AND METHODS: An Internet search for "cleft lip," "cleft palate," and "family information" was carried out using three search engines. Within each search, the first 25 relevant websites identified were downloaded and assessed for country of origin, authorship, domain, referencing, links, advertising, mention of orthodontics, illustrations, cleft-specificity, and content. Readability was determined using the Flesch Reading Ease Score, the Flesch-Kincaid Grade Level, and the Fog Scale Level. Data were analyzed by simple descriptive statistics. RESULTS: The initial search returned in excess of 1,800,000 hits. A total of 49 websites were evaluated, excluding repetitions, with a wide range of information available. The websites assessed were mostly of U.S. origin, with a .org domain, authored by universities/hospitals, not cleft-specific, without advertisements, contained links but not references, mentioned orthodontics even if to a small extent, contained some form of illustrations, and varied greatly in quantity and quality of information presented. A wide range of readability scores was obtained, equating to reading ages from fourth grade to university graduate level, with a mean reading age at the eighth to ninth grade level. CONCLUSIONS: Cleft lip and palate-related information for families on the Internet is variable in content, quality, and readability. Clinicians should have the responsibility to guide and help parents with website retrieval, while authors of websites should aim to keep information readable and relevant to family demands.

PMID 19115798

One-stage palate repair improves speech outcome and early maxillary growth in patients with cleft lip and palate

J Physiol Pharmacol. 2009 Dec;60 Suppl 8:37-41.

Pradel W, Senf D, Mai R, Ludicke G, Eckelt U, Lauer G.

Department of Oral and Maxillofacial Surgery, University Hospital Carl Gustav Carus, Dresden Technical University, Dresden, Germany. Abstract There are several types of palatal surgery; each cleft centre chooses its own technique based on experience and treatment philosophy. The aim of this study was to compare speech outcome and maxillary growth in children with cleft lip and palate deformity after palate repair with either a one-stage or a two- stage procedure and to identify the better treatment protocol. In 24 children, speech outcome was assessed regarding resonance, nasal escape, compensatory articulations, facial grimace, and spontaneous speech. In addition, plaster models of 15 children were compared. In 12 children, a two-stage procedure was performed (group A): at the age of 9-12 months, an intravelar veloplasty for repair of the soft palate, and at the age of 24-36 months a bipedicled flap closure of the hard palate. In 12 children, the same techniques were used in a one-stage procedure, at the age of 9-12 months (group B). The children of group B showed less altered resonance and less nasal emission at 4 years of age compared to the children of group A. At 6 years, the children of group A had improved their speech skills, but they did not equal the results of group B. In the study models of group A at age 6 years, the transverse dimension (anterior and posterior width of the dental arch) was smaller than in the models of group B. The one-stage repair of cleft palate at the age of 9-12 months seems to have a more positive influence on speech development and early maxillary growth than the two-stage procedure.

PMID: 20400790


A dosage-dependent role for Spry2 in growth and patterning during palate development

Mech Dev. 2007 Sep-Oct;124(9-10):746-61. Epub 2007 Jul 10.

Welsh IC, Hagge-Greenberg A, O'Brien TP.

Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA.

Abstract The formation of the palate involves the coordinated outgrowth, elevation and midline fusion of bilateral shelves leading to the separation of the oral and nasal cavities. Reciprocal signaling between adjacent fields of epithelial and mesenchymal cells directs palatal shelf growth and morphogenesis. Loss of function mutations in genes encoding FGF ligands and receptors have demonstrated a critical role for FGF signaling in mediating these epithelial-mesenchymal interactions. The Sprouty family of genes encode modulators of FGF signaling. We have established that mice carrying a deletion that removes the FGF signaling antagonist Spry2 have cleft palate. We show that excessive cell proliferation in the Spry2-deficient palate is accompanied by the abnormal progression of shape changes and movements required for medially directed shelf outgrowth and midline contact. Expression of the FGF responsive transcription factors Etv5, Msx1, and Barx1, as well as the morphogen Shh, is restricted to specific regions of the developing palate. We detected elevated and ectopic expression of these transcription factors and disorganized Shh expression in the Spry2-deficient palate. Mice carrying a targeted disruption of Spry2 fail to complement the craniofacial phenotype characterized in Spry2 deletion mice. Furthermore, a Spry2-BAC transgene rescues the palate defect. However, the BAC transgenic mouse lines express reduced levels of Spry2. The resulting hypomorphic phenotype demonstrates that palate development is Spry2 dosage sensitive. Our results demonstrate the importance of proper FGF signaling thresholds in regulation of epithelial-mesenchymal interactions and cellular responses necessary for coordinated morphogenesis of the face and palate.

PMID: 17693063


Anatomy of musculus levator veli palatini in the 15-week human fetus

Acta Anat (Basel). 1979;105(1):94-105.

Klueber K, Langdon HL.


The morphology of musculus levator veli palatini in the 15-week fetus was analyzed using 30-micrometer subserial sections. The sample included 26 specimens, of which 9 each were sectioned coronally and sagittally while 8 were sectioned in the transverse plane. At this stage of development m. levator veli palatini takes a general attachment to the precursor of the petrous part of the temporal bone, and, in some cases, auxiliary attachments to the auditory tube complex were also observed. At its origin, the muscle is located anterior to the tube. It then runs medially, passing beneath the auditory tube prior to entering the velum. As it nears the region of the lateral pharyngeal wall, a small fascicle trails posteriorly and inferiorly to the main muscle mass and occasionally runs into the upper margin of m. constrictor pharyngis superior. The levator muscle is more localized within the velum at this stage of development than it has been reported to be in the adult, being confined here to the central third of the soft palate. Most of the fibers of the muscle appear to form a sling within the central 20% of the velum, although some were seen to take attachment to loose connective tissue and the palatine raphe. Upon its entry into the velum, m. levator veli palatini is intersected vertically by bundles of both mm. palatoglossus and palatopharyngeus.

PMID 525252


Development and peripheral innervation of the palatal muscles. Acta Anat (Basel). 1977;97(1):4-14.

Doménech-Ratto G.

Following the observation of 51 embryos and human fetuses of between 9 and 190 mm vertex/coccys length, cut transversally, frontally, or sagittally, depending on the case, and coloured with HE, Azan, or by the Bielschowsky method, we studied the development, and peripheral innervation of the palatal muscles. We reached a series of conclusions which we put forward in this paper. The m. tensor veli palatini is the one which develops earliest. It derives from the sam blastematic mass as the muscles of mastication, and it is innervated by a branch of the n. mandibularis. The m. levator veli palatini and m. pharyngopalatinus coincide chronologically with the appearance of the m. cephalopharyngeus. They derive from the pharyngeal musculature, and are innervated by fibres proceeding from the n. glossopharyngeus, in the case of the first one, and, in the case of the second, by direct branches from the n. glossopharyngeus and n. vagus, which penetrate the muscle directly, without prior contact with any nerve plexus. The m. uvulae is first formed, at the time the palatine processes close. In the first place, two outlines may be seen; but after 50 mm approximately it is formed by one muscle only, on the medial line; it is innervated by branches which proceed from the posterior n. palatinus. The m. glossopalatinus is the last to appear. It is closely linked to the musculature of the tongue and, therefore, we think that it derives from the hypobranchial musculature, and that is innervated in the body of the tongue itself, by means of the n. hypoglossus.

PMID 66841

ICD - Cleft Palate

Q35.1 Q35.3 Q35.5 Q35.7 Q35.9
Q35 Cleft palate
Includes: fissure of palate

cleft palate with cleft lip ( [#q37 Q37.- ])

Cleft hard palate
Cleft soft palate
Cleft hard palate with cleft soft palate
Cleft uvula
Cleft palate, unspecified
Q36.0 Q36.1 Q36.9
Q36 Cleft lip
Includes: cheiloschisis
congenital fissure of lip
labium leporinum

cleft lip with cleft palate ( [#q37 Q37.- ])

Cleft lip, bilateral
Cleft lip, median
Cleft lip, unilateral
Cleft lip NOS

Q37 Cleft palate with cleft lip
Q37.0 Cleft hard palate with bilateral cleft lip
Q37.1 Cleft hard palate with unilateral cleft lip
Cleft hard palate with cleft lip NOS
Q37.2 Cleft soft palate with bilateral cleft lip
Q37.3 Cleft soft palate with unilateral cleft lip
Cleft soft palate with cleft lip NOS
Q37.4 Cleft hard and soft palate with bilateral cleft lip
Q37.5 Cleft hard and soft palate with unilateral cleft lip
Cleft hard and soft palate with cleft lip NOS
Q37.8 Unspecified cleft palate with bilateral cleft lip
Q37.9 Unspecified cleft palate with unilateral cleft lip
Cleft palate with cleft lip NOS