Talk:Abnormal Development - Cleft Palate

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Cite this page: Hill, M.A. (2019, October 16) Embryology Abnormal Development - Cleft Palate. Retrieved from


J Cell Biochem. 2019 May 9. doi: 10.1002/jcb.28888. [Epub ahead of print] Identification of circular RNA-associated competing endogenous RNA network in the development of cleft palate. Shu X1, Cheng L1, Dong Z1, Shu S1. Author information Abstract Circular RNAs (circRNAs) serve as competing endogenous RNAs (ceRNAs) and indirectly regulate gene expression through shared microRNAs (miRNAs). However, the regulatory mechanisms of circRNA as ceRNA associated with the fusion of palatal shelves in palatogenesis are yet unclear. This study aimed to explore the potential mechanism underlying the role of circRNA as ceRNA in cleft palate (CP). First, we systematically analyzed RNA-seq and miRNA-seq data after high-throughput sequencing for embryonic palatal shelf tissues from a mouse CP model induced by maternal exposure to all-trans retinoic acid on embryonic gestation day 14.5 (E14.5). Thirty-nine circRNAs, 18 miRNAs, and 936 messenger RNAs (mRNAs) were significantly dysregulated (log2 [fold change {FC}] > 1; P < 0.05). Thereafter, we constructed a circRNA-associated ceRNA network. Finally, we determined the circRNA_0954-miRNA-881-3p-PRKAR1α ceRNA network as a hub involved in palatogenesis. Gene Ontology analysis revealed that ceRNA-related genes were associated with facial morphogenesis and developmental gene silencing. Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated that ceRNA-related genes are involved in apoptosis (P < 0.05, fold enrichment >1). Quantitative reverse transcription polymerase chain reaction was performed to verify the results of ceRNA analysis. We found that the circRNA-miRNA-mRNA ceRNA network is involved in palatogenesis. The present results imply that circRNA_0954-miRNA-881-3p-PRKAR1α ceRNA network may cause dysfunctional palatal fusion and might facilitate the development of novel epigenetic biomarkers to treat CP in the future.

© 2019 Wiley Periodicals, Inc.

KEYWORDS: circular RNA; cleft palate; competing endogenous RNA; microRNA PMID: 31074068 DOI: 10.1002/jcb.28888


Constitutive activation of hedgehog signaling adversely affects epithelial cell fate during palatal fusion

Li J, Yuan Y, He J, Feng J, Han X, Jing J, Ho TV, Xu J & Chai Y. (2018). Constitutive activation of hedgehog signaling adversely affects epithelial cell fate during palatal fusion. Dev. Biol. , 441, 191-203. PMID: 29981310 DOI.

Li J1, Yuan Y2, He J3, Feng J2, Han X2, Jing J4, Ho TV2, Xu J2, Chai Y5. Author information Abstract Cleft palate is one of the most common craniofacial congenital defects in humans. It is associated with multiple genetic and environmental risk factors, including mutations in the genes encoding signaling molecules in the sonic hedgehog (Shh) pathway, which are risk factors for cleft palate in both humans and mice. However, the function of Shh signaling in the palatal epithelium during palatal fusion remains largely unknown. Although components of the Shh pathway are localized in the palatal epithelium, specific inhibition of Shh signaling in palatal epithelium does not affect palatogenesis. We therefore utilized a hedgehog (Hh) signaling gain-of-function mouse model, K14-Cre;R26SmoM2, to uncover the role of Shh signaling in the palatal epithelium during palatal fusion. In this study, we discovered that constitutive activation of Hh signaling in the palatal epithelium results in submucous cleft palate and persistence of the medial edge epithelium (MEE). Further investigation revealed that precise downregulation of Shh signaling is required at a specific time point in the MEE during palatal fusion. Upregulation of Hh signaling in the palatal epithelium maintains the proliferation of MEE cells. This may be due to a dysfunctional p63/Irf6 regulatory loop. The resistance of MEE cells to apoptosis is likely conferred by enhancement of a cell adhesion network through the maintenance of p63 expression. Collectively, our data illustrate that persistent Hh signaling in the palatal epithelium contributes to the etiology and pathogenesis of submucous cleft palate through its interaction with a p63/Irf6-dependent biological regulatory loop and through a p63-induced cell adhesion network. KEYWORDS: Palatal epithelial cell fate; Palatal fusion; Shh signaling; Submucous cleft palate PMID: 29981310 PMCID: PMC6152919 [Available on 2019-09-01] DOI: 10.1016/j.ydbio.2018.07.003


p63 exerts spatio-temporal control of palatal epithelial cell fate to prevent cleft palate

PLoS Genet. 2017 Jun 12;13(6):e1006828. doi: 10.1371/journal.pgen.1006828. eCollection 2017 Jun.

Richardson R1, Mitchell K1, Hammond NL1, Mollo MR2, Kouwenhoven EN3, Wyatt ND1, Donaldson IJ1, Zeef L1, Burgis T1, Blance R1, van Heeringen SJ3, Stunnenberg HG4, Zhou H3,5, Missero C2,6, Romano RA7, Sinha S8, Dixon MJ1, Dixon J1. Author information Abstract Cleft palate is a common congenital disorder that affects up to 1 in 2500 live births and results in considerable morbidity to affected individuals and their families. The aetiology of cleft palate is complex with both genetic and environmental factors implicated. Mutations in the transcription factor p63 are one of the major individual causes of cleft palate; however, the gene regulatory networks in which p63 functions remain only partially characterized. Our findings demonstrate that p63 functions as an essential regulatory molecule in the spatio-temporal control of palatal epithelial cell fate to ensure appropriate fusion of the palatal shelves. Initially, p63 induces periderm formation and controls its subsequent maintenance to prevent premature adhesion between adhesion-competent, intra-oral epithelia. Subsequently, TGFβ3-induced down-regulation of p63 in the medial edge epithelia of the palatal shelves is a pre-requisite for palatal fusion by facilitating periderm migration from, and reducing the proliferative potential of, the midline epithelial seam thereby preventing cleft palate. PMID: 28604778 PMCID: PMC5484519 DOI: 10.1371/journal.pgen.1006828


Meta-analysis Reveals Genome-Wide Significance at 15q13 for Nonsyndromic Clefting of Both the Lip and the Palate, and Functional Analyses Implicate GREM1 As a Plausible Causative Gene

PLoS Genet. 2016 Mar 11;12(3):e1005914. doi: 10.1371/journal.pgen.1005914. eCollection 2016 Mar.

Ludwig KU, Ahmed ST, Böhmer AC, Sangani NB, Varghese S, Klamt J, Schuenke H, Gültepe P, Hofmann A, Rubini M, Aldhorae KA, Steegers-Theunissen RP, Rojas-Martinez A, Reiter R, Borck G, Knapp M, Nakatomi M, Graf D, Mangold E, Peters H.


Nonsyndromic orofacial clefts are common birth defects with multifactorial etiology. The most common type is cleft lip, which occurs with or without cleft palate (nsCLP and nsCLO, respectively). Although genetic components play an important role in nsCLP, the genetic factors that predispose to palate involvement are largely unknown. In this study, we carried out a meta-analysis on genetic and clinical data from three large cohorts and identified strong association between a region on chromosome 15q13 and nsCLP (P = 8.13 × 10(-14) for rs1258763; relative risk (RR): 1.46, 95% confidence interval (CI): 1.32-1.61)) but not nsCLO (P = 0.27; RR: 1.09 (0.94-1.27)). The 5 kb region of strongest association maps downstream of Gremlin-1 (GREM1), which encodes a secreted antagonist of the BMP4 pathway. We show during mouse embryogenesis, Grem1 is expressed in the developing lip and soft palate but not in the hard palate. This is consistent with genotype-phenotype correlations between rs1258763 and a specific nsCLP subphenotype, since a more than two-fold increase in risk was observed in patients displaying clefts of both the lip and soft palate but who had an intact hard palate (RR: 3.76, CI: 1.47-9.61, Pdiff<0.05). While we did not find lip or palate defects in Grem1-deficient mice, wild type embryonic palatal shelves developed divergent shapes when cultured in the presence of ectopic Grem1 protein (P = 0.0014). The present study identified a non-coding region at 15q13 as the second, genome-wide significant locus specific for nsCLP, after 13q31. Moreover, our data suggest that the closely located GREM1 gene contributes to a rare clinical nsCLP entity. This entity specifically involves abnormalities of the lip and soft palate, which develop at different time-points and in separate anatomical regions.

PMID 26968009


Molecular basis of cleft palates in mice

World J Biol Chem. 2015 Aug 26;6(3):121-38. doi: 10.4331/wjbc.v6.i3.121.

Funato N1, Nakamura M1, Yanagisawa H1.

Abstract Cleft palate, including complete or incomplete cleft palates, soft palate clefts, and submucosal cleft palates, is the most frequent congenital craniofacial anomaly in humans. Multifactorial conditions, including genetic and environmental factors, induce the formation of cleft palates. The process of palatogenesis is temporospatially regulated by transcription factors, growth factors, extracellular matrix proteins, and membranous molecules; a single ablation of these molecules can result in a cleft palate in vivo. Studies on knockout mice were reviewed in order to identify genetic errors that lead to cleft palates. In this review, we systematically describe these mutant mice and discuss the molecular mechanisms of palatogenesis. KEYWORDS: Incomplete cleft palate; Knockout mice; Palatal shelf; Palatogenesis; Submucosal cleft palate; Tbx1

PMID 26322171

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


Is there an optimal resting velopharyngeal gap in operated cleft palate patients?

Indian J Plast Surg. 2013 Jan;46(1):87-91. doi: 10.4103/0970-0358.113716.

Yellinedi R1, Damalacheruvu MR.

Abstract CONTEXT: Videofluoroscopy in operated cleft palate patients. AIMS: To determine the existence of an optimal resting velopharyngeal (VP) gap in operated cleft palate patients. SETTINGS AND DESIGN: A retrospective analysis of lateral view videofluoroscopy of operated cleft palate patients. MATERIALS AND METHODS: A total of 117 cases of operated cleft palate underwent videofluoroscopy between 2006 and 2011. The lateral view of videofluoroscopy was utilised in the study. A retrospective analysis of the lateral view of videofluoroscopy of these 117 patients was performed to analyse the resting VP gap and its relationship to VP closure. STATISTICAL ANALYSIS USED: None. RESULTS: Of the 117 cases, 35 had a resting gap of less than 6 mm, 34 had a resting gap between 6 and 10 mm and 48 patients had a resting gap of more than 10 mm. CONCLUSIONS: The conclusive finding was that almost all the patients with a resting gap of <6 mm (group C) achieved radiological closure of the velopharynx with speech; thus, they had the least chance of VP insufficiency (VPI). Those patients with a resting gap of >10 mm (group A) did not achieve VP closure on phonation, thus having full-blown VPI. Therefore, it can be concluded that the ideal resting VP gap is approximately 6 mm so as to get the maximal chance of VP closure and thus prevent VPI. KEYWORDS: Resting gap; cleft palate; velopharyngeal incompetence; videofluoroscopy

PMID 23960311 PMCID: PMC3744913

velopharyngeal insufficiency (VPI) - occurs when the velum and lateral and posterior pharyngeal walls fail to separate the oral cavity from the nasal cavity during speech.

Table 1 :Neuromeric origins and developmental field defects of the Tessier craniofacial clefts

Tessier Zone Neuromere Origin Developmental Field Neurovascular Supply
0 n/a fusion failure


1 r2’ premaxilla- central incisor medial sphenopalatine
2 r2’ premaxilla-central, lateral incisors/frontal process medial sphenopalatine
3 r2 maxilla, palatine bone, inferior turbinate lateral sphenopalatine
4 r2
5 r2
6 r2
7 r2
8 r2
9 alisphenoid middle meningeal, anterior deep temporal r2
10 p5 postfrontal supraorbital
11 p5, r1 prefrontal, lacrimal supratrochlear, dorsal nasal
12 p5, r1 ethmoid labryinth anterior/posterior ethmoid, lateral nasal branches
13 p5, r1 ethmoid cribiform anterior/posterior ethmoid, medial nasal branches
14 n/a fusion failure n/a


Palatoplasty: evolution and controversies

Chang Gung Med J. 2008 Jul-Aug;31(4):335-45.

Leow AM1, Lo LJ.


Treatment of cleft palate has evolved over a long period of time. Various techniques of cleft palate repair that are practiced today are the results of principles learned through many years of modifications. The challenge in the art of modern palatoplasty is no longer successful closure of the cleft palate but an optimal speech outcome without compromising maxillofacial growth. Throughout these periods of evolution in the treatment of cleft palate, the effectiveness of various treatment protocols has been challenged by controversies concerning speech and maxillofacial growth. This article reviews the history of cleft palate surgery from its humble beginnings to modern-day palatoplasty, and describes various palatoplasty techniques and commonly used modifications. Current controversial issues on the timing of cleft palate repair, and the effects on speech and maxillofacial growth are also discussed. PMID 18935791