Palate Development

Introduction

Ultrasound - Cleft Lip

The palate has two key stages of development during embryonic (primary) and an early fetal (secondary) involving the fusion of structures and a key epithelial to mesenchymal transition.

The primary palate is formed by two parts:

1. maxillary components of the first pharyngeal arch (lateral)
2. frontonasal prominence (midline)

The secondary palate can also be divided in two anatomical parts:

1. anterior hard palate - ossified (contributions from the maxilla and palatine bones)
2. posterior soft palate - muscular.

The oral side of the palate is covered with a squamous stratified (pluristratified) epithelium. The surface of the hard palate of most mammalian species is further thrown into a series of palatal ridges or rugae palatinae, that are transversal ridges. Both the palatal ridge number and arrangement are also species specific.

Head Links: Introduction | Medicine Lecture | Medicine Lab | Science Lecture | Science Lab | Palate | Tongue | Placodes | Skull Development | Bone Histology | Head and Face Movies | Abnormalities | Category:Head

Historic Embryology: 1910 Skull | 1910 Skull Images | 1921 Human Brain Vascular | 1923 Head Subcutaneous Plexus | 1919 21mm Embryo Skull | 1920 Human Embryo Head Size | 1921 43 mm Fetal Skull | Historic Disclaimer

Some Recent Findings

Regulation of the Epithelial Adhesion Molecule CEACAM1 Is Important for Palate Formation "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. ...These results suggest that CEACAM1 has roles in the initiation of palatal fusion via epithelial cell adhesion." Role of GSK-3β in the Osteogenic Differentiation of Palatal Mesenchyme "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." Ephrin reverse signaling controls palate fusion via a PI3 kinase-dependent mechanism "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." A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4 "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." A dosage-dependent role for Spry2 in growth and patterning during palate development "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."

More recent papers

This table shows an automated computer PubMed search using the listed sub-heading term. Therefore the list of references do not reflect any editorial selection of material based on content or relevance. References appear in this list based upon the date of the actual page viewing. References listed on the rest of the content page and the associated discussion page (listed under the publication year sub-headings) do include some editorial selection based upon both relevance and availability. Links: References | Discussion Page | Pubmed Most Recent Search term: Cleft Palate Sibele Nascimento de Aquino, Ana Camila Messetti, Elizabete Bagordakis, Hercílio Martelli-Júnior, Mario Sergio Swerts, Edgard Graner, Ricardo D Coletta Polymorphisms in FGF12, VCL, CX43 and VAX1 in Brazilian patients with nonsyndromic cleft lip with or without cleft palate. BMC Med. Genet.: 2013, 14(1);53 PMID:23679094 Carrie Stransky, Marten Basta, Cynthia Solot, Marilyn Cohen, David W Low, Don Larossa, Oksana Jackson Do Pierre Robin Sequence Patients Have Worse Outcomes After Cleft Palate Surgery? Ann Plast Surg: 2013; PMID:23676521 Derek J Rogers, Jean E Ashland, Marie J Rozeboom, Christopher J Hartnick Modified superior pharyngeal flap for the treatment of velopharyngeal insufficiency in children. Int. J. Pediatr. Otorhinolaryngol.: 2013; PMID:23673163 Azeez Butali, Julian Little, Cécile Chevrier, Sylvian Cordier, Regine Steegers-Theunissen, Astanand Jugessur, Bola Oladugba, Peter A Mossey Folic acid supplementation use and the MTHFR C677T polymorphism in orofacial clefts etiology: An individual participant data pooled-analysis. Birth Defects Res. Part A Clin. Mol. Teratol.: 2013; PMID:23670871 Guanghui Li, Jianhua Wei, Xi Wang, Guofeng Wu, Dandan Ma, Bo Wang, Yanpu Liu, Xinghua Feng Three-dimensional facial anthropometry of unilateral cleft lip infants with a structured light scanning system. J Plast Reconstr Aesthet Surg: 2013; PMID:23664802 Search term: Palate Embryology Yah-Huei Wu-Chou, Lun-Jou Lo, Kuo-Ting Philip Chen, Chun-Shin Frank Chang, Yu-Ray Chen A combined targeted mutation analysis of IRF6 gene would be useful in the first screening of oral facial clefts. BMC Med. Genet.: 2013, 14(1);37 PMID:23510002 Plinio Arcuri, Luana Campos Images in clinical medicine. Torus mandibularis. N. Engl. J. Med.: 2013, 368(9);e11 PMID:23445112 Antonius J M Luijsterburg, Anna M Rozendaal, Christl Vermeij-Keers Classifying Common Oral Clefts: A New Approach After Descriptive Registration. Cleft Palate Craniofac. J.: 2013; PMID:23432103 C-P Chen, S-P Lin, Y-N Su, S-R Chern, J-W Su, C-C Lee, W Wang Partial trisomy 1q (1q42.13-->qter) and partial monosomy 6q (6q27-->qter) in a girl with single median maxillary central incisor, corpus callosum dysgenesis and developmental delay. Genet. Couns.: 2012, 23(4);447-55 PMID:23431743 Jun-Ichi Iwata, Akiko Suzuki, Richard C Pelikan, Thach-Vu Ho, Pedro A Sanchez-Lara, Mark Urata, Michael J Dixon, Yang Chai Smad4-Irf6 genetic interaction and TGF_-mediated IRF6 signaling cascade are crucial for palatal fusion in mice. Development: 2013; PMID:23406900

Textbooks

• The Developing Human: Clinically Oriented Embryology (8th Edition) by Keith L. Moore and T.V.N Persaud - Moore & Persaud Chapter Chapter 10 The Pharyngeal Apparatus pp201 - 240.
• Larsen’s Human Embryology by GC. Schoenwolf, SB. Bleyl, PR. Brauer and PH. Francis-West - Chapter 12 Development of the Head, the Neck, the Eyes, and the Ears pp349 - 418.

Movies

‎‎Face Development Page | Play

‎‎Palate (oral view) Page | Play

‎‎Palate (front view) Page | Play

‎‎Tongue Page | Play

‎‎Fetal Palate Page | Play

‎‎Cleft Lip 15 Week Page | Play

‎‎Cleft Lip 18 Week Page | Play

Links: Movies | Ultrasound

Development Overview

• week 4 - pharyngeal arch formation, first pharngeal arch contributes mandible and maxilla.
• week 6 - 7 - primary palate formation maxillary processes and frontonasal prominence.
• week 9 - secondary palate shelves fuse, separating oral and nasal cavities.

Embryonic Period

• (week 4) - pharyngeal arch formation in rostrocaudal sequence (1, 2, 3, 4 and 6)
• First pharyngeal arch - upper maxillary (pair) and lower mandibular prominences
• Late embryonic period - maxillary prominences fuse with frontonasal prominence forming upper jaw (maxilla and upper lip)

• 

  Week 5 Stage 16

• Stage17 em01.jpg

  Week 6 Stage 17

• 

  Week 6.5 Stage 18

• 

  Week 7 Stage 19

EM Links: Image - stage 16 | Image - stage 17 | Image - stage 18 | Image - stage 19 | Palate Development

Fetal Period

palatal shelves elevation palatal shelves midline fusion

‎‎Fetal Palate Page | Play

Pharyngeal Arch Components

Major features to identify for each: arch, pouch, groove and membrane. Contribute to the formation of head and neck and in the human appear at the 4th week. The first arch contributes the majority of upper and lower jaw structures.

Early Face and Pharynx

• Pharynx - begins at the buccopharyngeal membrane (oral membrane), apposition of ectoderm with endoderm (no mesoderm between)

Pharyngeal Arch Development

• branchial arch (Gk. branchia= gill)
• arch consists of all 3 trilaminar embryo layers
• ectoderm- outside
• mesoderm- core of mesenchyme
• endoderm- inside

Neural Crest

• Mesenchyme invaded by neural crest generating connective tissue components
• cartilage, bone, ligaments
• arises from midbrain and hindbrain region

Face Development

Begins week 4 centered around stomodeum, external depression at oral membrane

5 initial primordia from neural crest mesenchyme

• single frontonasal prominence (FNP) - forms forehead, nose dorsum and apex
• nasal placodes develop later bilateral, pushed medially
• paired maxillary prominences - form upper cheek and upper lip
• paired mandibular prominences - lower cheek, chin and lower lip

Frontonasal Process

The frontonasal process (FNP) forms the majority of the superior part of the early face primordia. It later fuses with the maxillary component of the first pharyngeal arch to form the upper jaw. Failure of this fusion event during the embryonic period leads to cleft lip. Under the surface ectoderm the process mesenchyme consists of two cell populations; neural crest cells, forming the connective tissues; and the mesoderm forming the endothelium of the vascular network.

A chicken developmental model study has identified a specific surface region, the Frontonasal Ectodermal Zone (FEZ), initially induced by bone morphogenetic proteins that appears to regulate the future growth and patterning of the frontonasal process. The specific frontonasal ectodermal zone was located in the frontonasal process ectoderm flanking a boundary between Sonic hedgehog (Shh) and Fibroblast growth factor 8 (Fgf8) expression domains.

Head Growth

• continues postnatally - fontanelle allow head distortion on birth and early growth
• bone plates remain unfused to allow growth, puberty growth of face

Embryonic Palate

Human primary palate

• develops between embryonic stages 15 and 18.
• fusion in the human embryo between stage 17 and 18, from an epithelial seam to the mesenchymal bridge.

Links: Carnegie stage 17 | Carnegie stage 18

Fetal Palate

Secondary palate, fusion in the human embryo in week 9. This requires the early palatal shelves growth, elevation and fusion during the early embryonic period. The fusion event is to both each other and the primary palate. palatal shelf elevation | secondary palate

Mouse Palatal Shelves

• E11 - protrude from bilateral maxillary processes
• E12.5 - secondary palatal development begins
• E12.5-E14 - grow vertically along the developing tongue
• E14.5 - they elevate, meet, and fuse at the midline, to form an intact palate shelf, reflex opening and closing movements of the mouth
• E15.5 - palatal fusion is complete, mesenchymal condensation followed by osteogenic differentiation occurs.

Links: Mouse Development

Molecular

Mouse - palate MMP-25 expression

Abnormalities

Cleft Palate - Australia (1981-1992)

The way in which the upper jaw forms from fusion of the smaller upper prominence of the first pharyngeal arch leads to a common congenital defect in this region called "clefting", which may involve either the upper lip, the palate or both structures.

International Classification of Diseases - Cleft Palate

Cleft lip and cleft palate (Q35-Q37)

Use additional code (Q30.2), if desired, to identify associated malformations of the nose. Excludes Robin's syndrome ( Q87.0 )

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

Embryonic Human Cleft Palate

Stage16 (ventral view)

Cleft Lip

International Classification of Diseases code 749.1 for isolated cleft lip and 749.2 for cleft lip with cleft palate. Australian national rate (1982-1992) 8.1 - 9.9 /10,000 births. Of 2,465 infants 6.2% were stillborn and 7.8% liveborn died during neonatal period. rate similar in singleton and twin births.

Cleft Palate

An 8 month old infant with an extensive cleft palate associated with Bamforth- Lazarus syndrome.

International Classification of Diseases code 749.0 Australian national rate (1982-1992) 4.8 - 6 /10,000 births. Of 1,530 infants 5.5% were stillborn and 11.5% liveborn died during neonatal period. slightly more common in twin births than singleton. (Data: Congenital Malformations Australia 1981-1992 P. Lancaster and E. Pedisich ISSN 1321-8352) Links: Development Animation - Palate 1 | Development Animation - Palate 2 | Orofacial Cleft with or without cleft palate Search Pubmed Now: cleft lip | cleft palate

Cleft Risk Variants

Two genes were identified from a recent genome-wide study.

• MAFB is expressed in the mouse palatal shelf.
• ABCA4 is a member of a superfamily of transmembrane proteins, and mutations in ABCA4 play a major role in the etiology of Stargardt disease and related retinopathies. Gene produces an ATP-binding cassette (ABC) superfamily trans-membrane protein

Links: OMIM - MAFB | OMIM - ABCA4

Ten most frequently reported Birth Anomalies

1. Hypospadias (More? Development Animation - Genital Male External | Genital Abnormalities - Hypospadia)
2. Obstructive Defects of the Renal Pelvis (More? Renal System - Abnormalities)
3. Ventricular Septal Defect (More? Cardiovascular Abnormalities - Ventricular Septal Defect)
4. Congenital Dislocated Hip (More? Musculoskelal Abnormalities - Congenital Dislocation of the Hip (CDH))
5. Trisomy 21 or Down syndrome - (More? Trisomy 21)
6. Hydrocephalus (More? Hydrocephalus)
7. Cleft Palate (More? Palate_Development)
8. Trisomy 18 or Edward Syndrome - multiple abnormalities of the heart, diaphragm, lungs, kidneys, ureters and palate 86% discontinued (More? (More? Trisomy 18)
9. Renal Agenesis/Dysgenesis - reduction in neonatal death and stillbirth since 1993 may be due to the more severe cases being identified in utero and being represented amongst the increased proportion of terminations (approximately 31%). (More? Renal System - Abnormalities)
10. Cleft Lip and Palate - occur with another defect in 33.7% of cases.(More? Palate Development | Head Development)

(From the Victorian Perinatal Data Collection Unit in the Australian state of Victoria between 2003-2004)

Folate

A recent study of periconceptional folate supplementation using the Cochrane Pregnancy and Childbirth Group's Trials Register (July 2010) identified no statistically significant evidence of any effects on prevention of cleft palate and cleft lip at birth.

References

Journals

• The Cleft Palate-Craniofacial Journal Homepage | Available issues

Reviews

Indian J Plast Surg. 2009 October; 42(Suppl):Cleft Lip and Palate Issue

L Meng, Z Bian, R Torensma, J W Von den Hoff Biological mechanisms in palatogenesis and cleft palate. J. Dent. Res.: 2009, 88(1);22-33 PMID:19131313

Marek Dudas, Wai-Yee Li, Jieun Kim, Alex Yang, Vesa Kaartinen Palatal fusion - where do the midline cells go? A review on cleft palate, a major human birth defect. Acta Histochem.: 2007, 109(1);1-14 PMID:16962647

M W Ferguson Palate development. Development: 1988, 103 Suppl();41-60 PMID:3074914

E D Hay An overview of epithelio-mesenchymal transformation. Acta Anat (Basel): 1995, 154(1);8-20 PMID:8714286

Articles

Gerd Steding, Yutao Jian The origin and early development of the nasal septum in human embryos. Ann. Anat.: 2010, 192(2);82-5 PMID:20149609

Wei Xiong, Fenglei He, Yuka Morikawa, Xueyan Yu, Zunyi Zhang, Yu Lan, Rulang Jiang, Peter Cserjesi, Yiping Chen Hand2 is required in the epithelium for palatogenesis in mice. Dev. Biol.: 2009, 330(1);131-41 PMID:19341725

Search PubMed

Search Pubmed: palate development | cleft palate development |

Additional Images

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  Nasal cavities and palate

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  Palate, tongue and Meckel's cartilage

• 

  Historic Pharynx cartoon

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  Ventral aspect of hard palate of human embryo of 80 mm

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  Unilateral cleft lip and palate

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  Mouse ruga pattern (E16)

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  Mouse - Spry1 cleft palate

Terms

• cleft - An anatomical gap or space occuring in abnormal development in or between structures. Most commonly associated with cleft lip and cleft palate. Term is also used to describe the external groove that forms between each pharyngeal arch during their formation.

• cleft lip - An abnormality of face development leading to an opening in the upper lip. Clefting of the lip and or palate occurs with 300+ different abnormalities. Depending on many factors, this cleft may extend further into the oral cavity leading to a cleft palate. In most cases clefting of the lip and palate can be repaired by surgery.

• cleft palate - An abnormality of face development leading to an opening in the palate, the roof of the oral cavity between the mouth and the nose. Clefting of the lip and or palate occurs with 300+ different abnormalities. In most cases clefting of the lip and palate can be repaired by surgery. Palate formation in the embryo occurs at two distinct times and developmental processes called primary and secondary palate formation. This leads to different forms (classifications) and degrees of clefting.

• epithelial mesenchymal transition - (EMT, epitheliomesenchymal transformation) conversion of an epithelium into a mesenchymal (connective tissue) cellular organization.

• epitheliomesenchymal transformation - (epithelial mesenchymal transition) conversion of an epithelium into a mesenchymal (connective tissue) cellular organization.

• medial edge epithelial - (MEE) opposing palatal shelves adhere to each other to form this epithelial seam.

• palate - The roof of the mouth (oral cavity) a structure which separates the oral from the nasal cavity. Develops as two lateral palatal shelves which grow and fuse in the midline. Initally a primary palate forms with fusion of the maxillary processes with the nasal processes in early face formation. Later the secondary palate forms the anterior hard palate which will ossify and separate the oral and nasal cavities. The posterior part of the palate is called the soft palate (velum, muscular palate) and contains no bone. Abnormalities of palatal shelf fusion can lead to cleft palate.

• palatogenesis - The process of palate formation, divided into primary and secondary palate development.

• pharyngeal arch - (branchial arch, Greek, branchial = gill) These are a series of externally visible anterior tissue bands lying under the early brain that give rise to the structures of the head and neck. In humans, five arches form (1,2,3,4 and 6) but only four are externally visible on the embryo. Each arch has initially identical structures: an internal endodermal pouch, a mesenchymal (mesoderm and neural crest) core, a membrane (endoderm and ectoderm) and external cleft (ectoderm). Each arch mesenchymal core also contains similar components: blood vessel, nerve, muscular, cartilage. Each arch though initially formed from similar components will differentiate to form different head and neck structures.

• philtrum - (infranasal depression, Greek, philtron = "to love" or "to kiss") Anatomically the surface midline vertical groove in the upper lip. Embryonically formed by the fusion of the frontonasal prominence (FNP) with the two maxillary processes of the first pharyngeal arch. Cleft palate (primary palate) occurs if these three regions fail to fuse during development. Fetal alcohol syndrome is also indicated by flatness and extension of this upper lip region.

• T-box 22 - (TBX22) a transcription factor that cause X-linked cleft palate and ankyloglossia in humans. Tbx22 is induced by fibroblast growth factor 8 (FGF8) in the early face while bone morphogenic protein 4 (BMP4) represses and therefore restricts its expression. (More? OMIM - TBX22)

• Transforming Growth Factor-beta - (TGFβ) factors induces both epithelial mesenchymal transition and/or apoptosis during palatal medial edge seam disintegration.

External Links

External Links Notice - The dynamic nature of the internet may mean that some of these listed links may no longer function. If the link no longer works search the web with the link text or name.

• Prof Virginia Diewert - Professor of Orthodontics, University of British Columbia, who recently visited the Lab and helped with content, organisation and development of the Palate Development section.
• Medline Plus - Cleft Lip and Palate
• Better Health Channel - Cleft palate and cleft lip
• March of Dimes Birth Defects Foundation - Cleft Palate

Glossary Links

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Dr Mark Hill 2013, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G