Review
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Biol Chem. Aug 26, 2015; 6(3): 121-138
Published online Aug 26, 2015. doi: 10.4331/wjbc.v6.i3.121
Molecular basis of cleft palates in mice
Noriko Funato, Masataka Nakamura, Hiromi Yanagisawa
Noriko Funato, Masataka Nakamura, Research Center for Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
Hiromi Yanagisawa, Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, United States
Hiromi Yanagisawa, Life Science Center of Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan
Author contributions: Funato N contributed to the conception and design of the manuscript, to the data analysis, and drafted the manuscript; Nakamura M and Yanagisawa H contributed to the interpretation of data, and revised the manuscript.
Supported by The Japan Society for the Promotion of Science (JSPS) through KAKENHI grants 25670774 and 15K11004, awarded to Funato N.
Conflict-of-interest statement: The authors declare no conflicts of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Noriko Funato, DDS, PhD, Research Center for Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan. noriko-funato@umin.ac.jp
Telephone: +81-3-58035796 Fax: +81-3-58030203
Received: April 21, 2015
Peer-review started: April 22, 2015
First decision: May 13, 2015
Revised: May 26, 2015
Accepted: July 11, 2015
Article in press: July 14, 2015
Published online: August 26, 2015

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.

Key Words: Tbx1, Submucosal cleft palate, Incomplete cleft palate, Palatal shelf, Palatogenesis, Knockout mice

Core tip: Cleft lip and/or palate is one of the most frequent congenital craniofacial anomalies observed. Multifactorial conditions, including genetic and environmental factors, induce the formation of cleft palates. We screened knockout mice with cleft palate phenotypes and observed approximately 180 mice with the anomaly. In order to understand the molecular regulatory mechanisms of palatogenesis and to identify genetic errors that lead to cleft palates, we aimed to review studies performed using knockout mice with cleft palates.



INTRODUCTION

Cleft lip and/or palate (CL/P) is the most frequent congenital craniofacial anomaly observed in humans, with an incidence of 1 per 700 births worldwide[1]. Furthermore, 55% of the patients with CL/P are reported to have a multiple malformation syndrome[2]. CL/P involves a multifactorial etiology, both genetic and environmental. Teratogens that cause CL/P in humans include common environmental exposures, such as alcohol, smoking, infections, dioxin, estrogen, retinoic acid, and altitude (reviewed by Murray[1]). The offspring of parents with CL/P present a higher incidence of CL/P than those without a family history[1]. Gene-environment interactions for non-syndromic CL/P have also been reported[1]. Cleft palate (CP) cases include complete CP, incomplete CP, and soft palate clefts. The mildest form of cleft palates is the soft palate cleft or bifid uvula because the initial palatal fusion occurs in the anterior region of secondary palatal shelves. Incomplete CP and soft palate clefts can manifest together with submucosal CP. This review focuses on studies performed using knockout mice with CP, aiming to clarify the molecular regulatory mechanisms of palatogenesis and to identify genetic errors underlying mammalian cleft palates.

MAMMALIAN PALATOGENESIS

The palate is formed with the primary and secondary palate. The primary palate is derived from the frontonasal prominence and becomes a small anterior part of the adult hard palate. The secondary palatal shelves extend bilaterally from the internal aspects of the maxillary prominences and will become the adult hard and soft palates. The process of palatogenesis consists of several stages: palatal shelf formation, elevation, and midline fusion of the palatal shelves (Figure 1). The secondary palatal shelves develop between embryonic day (E) 11.5 and 12.5 in the mouse embryo (Figure 1A). At E13.5, the palatal shelves grow downward on each side of the tongue (Figure 1B). As the jaws develop, the tongue descends and the palatal shelves elevate to a horizontal position above the dorsum of the tongue (E14). Continuing their growth, the bilateral palatal shelves meet at the midline and fuse between E14.5 and E15.5 (Figure 1C).

Figure 1
Figure 1 Palatogenesis in mice. Hematoxylin and eosin staining of coronal sections of the head of a wild-type mouse at embryonic day (E) 12.5 (A), E13.5 (B), and E14.5 (C, D). A: Mouse palatal shelves (p) develop from the maxillary prominences; B: By E13.5, the palatal shelves grow downward on each side of the tongue (t); C and D: At E14.5, the palatal shelves face each other along the midline above the tongue and fuse, separating the oral cavity (oc) from the nasal cavity (nc). The arrow in (D) indicates the medial edge epithelial (MEE) cells that constitute the midline epithelial seam. All animal experimental procedures were reviewed and approved by the Institutional Animal Care and Use Committees of the University of Texas Southwestern Medical Center and Tokyo Medical and Dental University. mes: Mesenchyme; epi: Epithelium.

The palatal shelves are composed of the neural crest-derived mesenchyme and ectoderm-derived epithelia, which cover the palatal mesenchyme (Figure 1D). Both elevation and fusion of the secondary palatal shelves occur in the midline from anterior to posterior. The secondary palatal shelves also fuse with the primary palate, separating the oral and nasal cavities. The anterior two-thirds of the palate forms the hard palate with neural crest-derived palatal bones (Figure 2A). The posterior one-third of the palate forms the bone-free soft palate and is involved in the palatopharyngeal sealing. Disruption at any stage of the formation, elevation, growth, or fusion of the secondary palatal shelves results in CP[3].

Figure 2
Figure 2 View of the palate from wild-type and Tbx1-/- mice with cleft palates. A-D: Ventral view of the maxilla of newborn wild-type (A) and Tbx1-/- mice with cleft palates (B-D). The palate consists of the primary palate (pp) and the secondary palate (sp), which consists of a hard palate (hp) and a soft palate (sp) (A). Tbx1-/- mice show complete cleft palate (CP) (arrowheads in B), incomplete CP (dashed line in C), and soft palate clefts associated with anterior CP (dashed line in D). An anterior CP (an arrow in D) is present at the junction between the primary palate and secondary palate, while the posterior palate remains fused; E-G: Ventral view of the cranial base of newborn wild-type (E) and Tbx1-/- mice (F, G) stained with alizarin red for mineralized bone and alcian blue for cartilage. Fusion of the bilateral palatal bones (pa) observed in the wild-type (dashed line in E) is absent in Tbx1-/- mice (dashed lines in F, G). The palatal shelves in the maxilla (mx) of Tbx1-/- mice with complete CP (oval dashed line in F) failed to grow toward the midline. Note the visible presphenoid bone (ps) associated with CP (F, G). Modified and used with permission from Funato et al[4]. ns: Nasal septum; pt: Pterygoid bone.
MOUSE MODELS FOR STUDYING THE MOLECULAR MECHANISMS OF PALATAL DEVELOPMENT

Major advances have been achieved regarding the molecular mechanisms that regulate palatal development using genetically engineered mice. Deletions in many genes of mice result in CP and the most frequent phenotype seen is complete CP (Figure 2B). Uniquely, Tbx1-/- mice present various phenotypes of CP[4], including complete CP (Figure 2B), incomplete CP (Figure 2C), and anterior CP (Figure 2D). Bone staining showed that some mice potentially had a submucosal CP (Figure 2G). These observations are in agreement with various CP phenotypes in humans.

In order to elucidate the molecular pathogenesis of CL/P, we conducted a literature search on PubMed (http://www.ncbi.nlm.nih.gov/pubmed) and the Mouse Genome Informatics (MGI) from the Jackson Laboratory (http://www.informatics.jax.org). The search was limited to knockout mice with CP and excluded the teratogen-induced CP (Table 1). We also investigated diseases/syndromes using the Online Mendelian Inheritance in Man (OMIM) (http://omim.org). Not all the molecules involved in cleft palates in mice are correlated to CL/P in human (Table 1). When genes in Table 1 were analyzed by biological function using BioCarta (http://www.biocarta.com) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway Database (http://www.genome.jp/kegg/pathway.html), the transforming growth factor (TGF), hedgehog, Wnt, fibroblast growth factor (FGF), and mitogen-activated protein kinase (MAPK) signaling pathways were found to be critical in palatogenesis (Table 2). When genes were analyzed by molecular function using the PANTHER (Protein ANalysis THrough Evolutionary Relationships) database (http://pantherdb.org)[5], the most significantly enriched molecular function was the “transcription factor”, especially the “homeobox transcription factors” (Table 2 and Figure 3).

Table 1 Molecules involved in cleft palate in mice.
Knockout mice with cleft palates
Humans
Gene/categoryProteinRef.OMIMSyndromeCL/P
Growth factors, antagonist, and receptors
Acvr1/Alk2Activin A receptor, type I[33]1102576Fibrodysplasia ossificans progressivanr
(Wnt1-Cre-mediated ablation)
Acvr2aActivin A receptor, type IIA[34]1102581nrnr
Bmp4Bone morphogenetic protein 4[35]1112262Microphthalmia, syndromic 6r
Orofacial cleft 11
Bmp7Bone morphogenetic protein 7[36]1112267nrnr
Bmpr1a/Alk3Bone morphogenetic protein receptor, type IA[35]1601299Juvenile polyposis syndrome,nr
(Nestin-Cre-mediated ablation)Polyposis syndrome
ChrdChordin[37]1603475nrnr
CtgfConnective tissue growth factor[38]1121009nrnr
Edn1Endothelin 1[39]2131240Auriculocondylar syndrome 3r
EgfrEpidermal growth factor receptor[17]1131550nrnr
Fgf9Fibroblast growth factor 9[40]1600921ucnr
Fgf10Fibroblast growth factor 10[13,41]1602115Aplasia of lacrimal and salivary glandsnr
LADD syndrome
Fgf18Fibroblast growth factor 18[42,43]1603726nrnr
Fgfr1Fibroblast growth factor receptor 1[44]1136350Nonsyndromic cleft lip/palater
Hartsfield syndrome
Hypogonadotropic hypogonadism 2
Pfeiffer syndrome
Fgfr2Fibroblast growth factor receptor 2[13,45]1176943Apert syndromer
(knockout) (Krt14-Cre-mediated ablation)Crouzon syndrome
Pfeiffer syndrome
Saethre-Chotzen syndrome
FstFollistatin[46]1136470nrnr
Gabrb3Gamma-aminobutyric acid A receptor, beta 3[47]1137192Epilepsy, childhood absence, susceptibility to, 5r
Gdf11/Bmp11Growth differentiation factor 11[48]1603936nrnr
Gpr124G protein-coupled receptor 124[49]1606823nrnr
InhbaInhibin, beta A/activin A[50]1147290nrnr
PdgfcPlatelet-derived growth factor C[51]1608452nrr [52]
PdgfraPlatelet-derived growth factor receptor, alpha polypeptide[53,54]1173490Gastrointestinal stromal tumor, somaticr
(knockout) (Wnt1-Cre-mediated ablation)Hypereosinophilic syndrome, idiopathic, resistant to imatinib
Tgfb2Transforming growth factor, beta 2[55]1190220Loeys-Dietz syndrome, type 4r
Tgfb3Transforming growth factor, beta 3[15,16,18]1190230Arrhythmogenic right ventricular dysplasia 1r
Tgfbr1/Alk5Transforming growth factor, beta receptor I[56,57]1190181Loeys-Dietz syndrome, type 1r
(Wnt1-Cre-, and Nestin-Cre-mediated ablation)
Tgfbr2Transforming growth factor, beta receptor II[12,58]1190182Loeys-Dietz syndrome, type 2r
(Wnt1-Cre-, and KRT14-Cre-mediated ablation)
VegfaVascular endothelial growth factor A[59]2192240nrnr
Membrane proteins
Ceacam1Carcinoembryonic antigen-related cell adhesion molecule 1[60]1109770nrnr
Efna5Ephrin A5[61]1601535nrnr
Efnb1Ephrin B1[62]1300035Craniofrontonasal dysplasiar
Efnb2Ephrin B2[63]1600527nrnr
Fzd2Frizzled class receptor 2[64]1600667nrnr
Itga5Integrin alpha 5[65,66]1135620nrnr
(knockout) (Mesp1-Cre-mediated ablation)
Itgb1Integrin beta 1[67]1135630nrnr
(Col2a1-Cre-mediated ablation)
Itgb8Integrin beta 8[68]1604160nrnr
Jag1Jagged1[69]2601920Alagille syndromenr
(Wnt1-Cre-mediated ablation)
Jag2Jagged2[70]1602570nrnr
Kcnj2Potassium inwardly-rectifying channel, subfamily J, member 2[71]1600681Andersen syndromer
Atrial fibrillation, familial, 9
Short QT syndrome 3
Lrp6Low density lipoprotein receptor-related protein 6[72]1603507nrnr
Ror2Receptor tyrosine kinase-like orphan receptor 2[73]1602337Robinow syndrome, autosomal recessiver
Brachydactyly, type B1
RykReceptor-like tyrosine kinase[74]1600524nrnr
Ryr1Ryanodine receptor 1, skeletal muscle[75]1180901Central core diseasenr
King-Denborough syndrome
Minicore myopathy with external ophthalmoplegia
Sc5d/Sc5dlSterol-C5-desaturase (fungal ERG3, delta-5-desaturase) homolog (S. cerevisae)[76]1602286Lathosterolosisnr
ShhSonic hedgehog[13,77]1600725Holoprosencephaly-3r
(KRT14-Cre-, and Sox2-Cre-mediated ablation)Microphthalmia with coloboma 5
Single median maxillary central incisor
Smo/SmohSmoothened, frizzled class receptor[78]1601500Basal cell carcinoma, somaticnr
(Wnt1-Cre-mediated ablation)
Tctn2Tectonic family member 2[79]1613846Meckel syndrome 8r
Wls/Gpr177Wntless homolog (Drosophila)[80]1611514nrnr
(Wnt1-Cre-mediated ablation)
Wnt5aWingless-type MMTV integration site family, member 5A[81]1164975Robinow syndrome, autosomal dominantr
Wnt9bWingless-type MMTV integration site family, member 9B[82,83]1602864nrnr
(knockout) (Foxg1-Cre-mediated ablation)
Transcription and nucleolar factors
Alx1Aristaless-like homeobox 1[84]1601527Frontonasal dysplasia 3r
Alx3Aristaless-like homeobox 3[85]1606014Frontonasal dysplasia 1r
Alx4Aristaless-like homeobox 4[85]1605420Frontonasal dysplasia 2Cleft alae nasi
Parietal foramina 2
Craniosynostosis 5
Anp32bAcidic (leucine-rich) nuclear phosphoprotein 32 family, member B[86]nrnrnr
Arid5AT-rich interaction domain-containing protein 5A[87]1611583nrnr
Asxl1Additional sex combs like 1[88]1612990Bohring-Opitz syndromer
Myelodysplastic syndrome, somatic
Barx1BarH-like homeobox 1[89]1603260nrnr
Cdc42Cell division cycle 42[90]1116952nrnr
(Prrx1-Cre-mediated ablation)
Chd7Chromodomain helicase DNA binding protein 7[91,92]1608892CHARGE syndromer
(heterozygotes) (Wnt1-Cre-mediated ablation)Hypogonadotropic hypogonadism 5 with or without anosmia
Cited2CBP/p300-interacting transactivator, with Glu/Asp-rich C-terminal domain, 2[93]1602937Atrial septal defect 8nr
Ventricular septal defect 2
Crebbp/CbpCREB binding protein[94]1600140Rubinstein-Taybi syndromenr
Dlx1Distal-less homeobox 1[95]1600029nrnr
Dlx2Distal-less homeobox 2[95]1126255nrnr
Dlx5Distal-less homeobox 5[96,97]1600028Split-hand/foot malformation 1 with sensorineural hearing lossr
Dph1/Ovca1DPH1 homolog (S. cerevisiae)[98]1603527nrnr
Eya1Eyes absent 1 homolog (Drosophila)[99]1601653Branchiootic syndrome 1r
Branchiootorenal syndrome 1, with or without cataracts
Anterior segment anomalies with or without cataract
Foxc2/Mfh1Forkhead box C2[100]1602402Lymphedema-distichiasis syndromer
Foxd3Forkhead box D3[101]1611539ucnr
(Wnt1-Cre-mediated ablation)
Foxe1/Titf2/Fkhl15Forkhead box E1[102]1602617Bamforth-Lazarus syndromer
Nonsyndromic orofacial clefting
Foxf2Forkhead box F2[103]1603250nrnr
Gbx2Gastrulation brain homeobox 2[104]1601135nrnr
Gli2GLI family zinc finger 2[8]1165230Culler-Jones syndromer
Holoprosencephaly-9
Gli3GLI family zinc finger 3[105]1165240Greig cephalopolysyndactyly syndromer
Pallister-Hall syndrome
GscGoosecoid homeobox[106]1138890Short stature, auditory canal atresia, mandibular hypoplasia, skeletal abnormalitiesnr
Hand2/dHandHeart and neural crest derivatives expressed 2[107]1602407nrnr
Hic1Hypermethylated in cancer 1[108]1603825nrnr
Hoxa2Homeobox A2[19]1604685Microtia with or without hearing impairment (AD)r
Microtia, hearing impairment, and cleft palate (AR)
Irf6Interferon regulatory factor 6[109,110]1607199van der Woude syndromer
Orofacial cleft 6
Popliteal pterygium syndrome 1
Jmjd6/PtdsrJumonji domain containing 6[111]1604914nrnr
Kat6a/Moz/Myst3K (lysine) Acetyltransferase 6A[112]1601408nrnr
Lhx7LIM homeobox gene 7[113]nrnrnr
Lhx8LIM homeobox gene 8[11]1604425nrr
Luzp1Leucine zipper protein 1[114]1601422nrnr
Mef2cMADS box transcription enhancer factor 2[115]1600662Chromosome 5q14.3 deletion syndromenr
(Wnt1-Cre-mediated ablation)Mental retardation, stereotypic movements, epilepsy, and/or cerebral malformations
Meox2Mesenchyme homeobox 2[116]1600535nrnr
Mn1Meningioma 1[117]1156100Meningiomanr
MntMax binding protein[118]1603039nrnr
Msx1Msh homeobox 1[10,23]1142983Ectodermal dysplasia 3, Witkop typer
Orofacial cleft 5
Tooth agenesis, selective, 1, with or without orofacial cleft
Msx2Msh homeobox 2[119]1123101Craniosynostosis, type 2r
(missense mutation)Parietal foramina 1
Parietal foramina with cleidocranial dysplasia
Nabp2/Obfc2b/hSSB1Nucleic acid binding protein 2[120,121]1612104nrnr
Osr2Odd-skipped related transcription factor 2[9]1611297nrr
Pak1ip1PAK1 interacting protein 1[122]1607811nrnr
Pax9Paired box gene 9[6]1167416Tooth agenesis, selective, 3nr
Pbx1Pre B cell leukemia homeobox 1[83]1176310Leukemia, acute pre-B-cellnr
Pds5aPDS5, regulator of cohesion maintenance, homolog A (S. cerevisiae)[123]1613200nrnr
Phc1/Rae28Polyhomeotic homolog 1[124]1602978ucnr
Pitx1Paired-like homeodomain 1[7,125]1602149Clubfoot, congenital, with or without deficiency of long bones and/or mirror-image polydactylyr
Liebenberg syndrome
Pitx2Paired-like homeodomain 2[126]1601542Axenfeld-Rieger syndrome, type 1nr
Iridogoniodysgenesis, type 2
Peters anomaly
PnnPinin[127]1603154nrnr
Prdm16PR domain containing 16[128]1605557Cardiomyopathy, dilated, 1LLnr
Left ventricular noncompaction 8
Prrx1/Prx1/MhoxPaired related homeobox 1[129]1167420Agnathia-otocephaly complexr
Ptch1/Ptc1Patched 1[130]1601309Basal cell nevus syndromer
(Wnt1-Cre-mediated ablation)(Gorlin syndrome)
Holoprosencephaly type 7
Pygo2Pygopus 2[131]1606903nrnr
(CMV-Cre-mediated ablation)
RaxRetina and anterior neural fold homeobox[132]1601881Microphthalmia, isolated 3nr
Recql4RecQ protein-like 4[133]1603780Baller-Gerold syndromer
RAPADILINO syndrome
Rothmund-Thomson syndrome
Runx2Runt-related transcription factor 2[134]1600211Cleidocranial dysplasiar
Sall3Spalt-like transcription factor 3[24]1605079nrnr
Satb2SATB homeobox 2[135,136]1608148Glass syndromer
Shox2Short stature homeobox 2[22]1602504nrnr
Sim2Single-minded family bHLH transcription factor 2[137]1600892nrnr
Smad4 (Osr2-Cre-mediated ablation)SMAD family member 4[138]1600993Juvenile polyposis/hereditary hemorrhagic telangiectasia syndromenr
Myhre syndrome
Smad7SMAD family member 7[139]1602932ucnr
Snai2Snail family zinc finger 2[140]1602150Piebaldismnr
Waardenburg syndrome, type 2D
Sox5SRY (sex determining region Y)-box 5[141]1604975nrnr
Sox9 (heterozygous)SRY (sex determining region Y)-box 9[142,143]1608160Acampomelic campomelic dysplasiar
(Wnt1-Cre-mediated ablation)
Sox11SRY (sex determining region Y)-box 11[144]1600898Mental retardation, autosomal dominant, 27nr
Sp8Sp8 transcription factor[145]1608306nrnr
Tshz1Teashirt zinc finger family member 1[146]1614427Aural atresia, congenitalnr
Tbx1T-box 1[4,147]1602054DiGeorge syndromer
(knockout) (KRT14-Cre-mediated ablation)Velocardiofacial syndrome
Conotruncal anomaly face syndrome
Tetralogy of Fallot
Tbx2T-box 2[148]1600747nrnr
Tbx22T-box 22[149]1300307Cleft palate with ankyloglossiar
submucous cleft palate (SMCP)
Tcof1Treacher Collins-Franceschetti syndrome 1[150]1606847Treacher-Collins syndromer
(heterozygous)
Tfap2ATranscription factor AP-2 alpha[151]1107580Branchio-oculo-facial syndromer
(Wnt1-Cre-mediated ablation)
Trp63/Tp63Transformation related protein p63[152]1603273Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3r
Orofacial cleft 8
Hay-Wells syndrome
Limb-mammary syndrome
Vax1Ventral anterior homeobox 1[153]1604294Microphthalmia, syndromic 11r
Whsc1Wolf-Hirschhorn syndrome candidate 1[154]1602952nrnr
Zeb1Zinc finger E-box binding homeobox 1[155]1189909Corneal dystrophynr
Zfp640/Mzf6dZinc finger protein 640[87]nrnrnr
Zic3Zinc finger protein of the cerebellum 3[156]1300265Congenital heart defects, nonsyndromicr
Heterotaxy, visceral, 1
VACTERL association
Cytoplasmic proteins
Akap8/Akap95A kinase (PRKA) anchor protein 8[157]1604692nrnr
Apaf1Apoptotic peptidase activating factor 1[158]1602233nrnr
B9d1B9 protein domain 1[159]1614144Meckel syndrome 9nr
CaskCalcium/calmodulin-dependent serine protein kinase[160]1300172FG syndrome 4r
Mental retardation and microcephaly with pontine and cerebellar hypoplasia
Cdkn1c/p57kip2Cyclin-dependent kinase inhibitor 1C[161,162]1600856Beckwith-Wiedemann syndromer
IMAGe syndrome
Chuk/Ikk1/Tcf16Conserved helix-loop-helix ubiquitous kinase[163]1600664Cocoon syndromenr
Crkv-crk sarcoma virus CT10 oncogene homolog[164]1164762nrnr
Ctnnb1Catenin (cadherin-associated protein), beta 1,[165,166]1116806Mental retardation, autosomal dominant 19nr
(KRT14-Cre-mediated ablation)
Cyp26B1Cytochrome P450, family 26, subfamily b, polypeptide 1[167]1605207Craniosynostosis with radiohumeral fusions and other skeletal and craniofacial anomaliesnr
Cyp51Cytochrome P450, family 51[168]1601637nrnr
Dhcr77-dehydrocholesterol reductase[169,170]1602858Smith-Lemli-Opitz syndromer
Dhrs3Dehydrogenase/reductase (SDR family) member 3[171,172]1612830nrnr
Dicer1Dicer 1, ribonuclease type III[29]1606241Rhabdomyosarcoma, embryonal, 2nr
(Pax2-Cre-mediated ablation)Goiter, multinodular 1
Pleuropulmonary blastoma
Dlg1/Dlgh/Sap97Discs large 1[173]1601014nrnr
FuzFuzzy planar cell polarity protein[174]1610622Neural tube defectsnr
Gab1Growth factor receptor bound protein 2-associated protein 1[175]1604439nrnr
Gad1/Gad67Glutamate decarboxylase 1[176,177]1605363Cerebral palsy, spastic quadriplegic, 1r
GlceGlucuronyl C5-epimerase[178]1612134nrnr
Glg1Golgi apparatus protein 1[179]1600753nrnr
Grb2Growth factor receptor bound protein 2[180]1108355nrnr
Gsk3bGlycogen synthase kinase 3 beta[181]1605004nrnr
Hs2st1Heparan sulfate 2-O-sulfotransferase 1[182]1604844nrnr
Hspb11/Ift25Heat shock protein family B (small), member 11[183]1604844nrnr
IlkIntegrin linked kinase[184]1602366nrnr
(Col2a1-Cre-mediated ablation)
Impad1/JawsInositol monophosphatase domain containing 1[185]1614010Chondrodysplasia with joint dislocations, GRAPP typer
Inpp5eInositol polyphosphate-5-phosphatase E[186]1613037Joubert syndrome 1nr
Mental retardation, truncal obesity, retinal dystrophy, and micropenis
Kif3aKinesin family member 3A[187]1604683nrnr
(Wnt1-Cre-mediated ablation)
Map3k7/Tak1Mitogen-activated protein kinase kinase kinase 7[188,189]1602614nrnr
(Wnt1-Cre-mediated ablation)
Nprl3Nitrogen permease regulator-like 3[190]1600928nrnr
Ofd1Oral-facial-digital syndrome 1 gene homolog (human)[191]1300170Joubert syndrome 10r
(CAG-Cre-mediated ablation)Orofaciodigital syndrome I
Simpson-Golabi-Behmel syndrome, type 2
Pdss2Prenyl (solanesyl) diphosphate synthase, subunit 2[192]1610564Coenzyme Q10 deficiency, primary, 3nr
(Pax2-Cre-mediated ablation)
PigaPhosphatidylinositol glycan anchor biosynthesis, class A[193]1311770Multiple congenital anomalies-hypotonia-seizures syndrome 2 Paroxysmal nocturnal hemoglobinuria, somaticnr
(EIIa-Cre-mediated ablation)
Pkdcc/VlkProtein kinase domain containing, cytoplasmic[194,195]1614150nrnr
(Sox2-Cre-mediated ablation)
Prickle1Prickle homolog 1[196]1608500Epilepsy, progressive myoclonic 1Bnr
Rad23bRAD23b homolog (S. cerevisiae)[197]1600062nrnr
Rspo2R-spondin 2 homolog (Xenopus laevis)[198,199]1610575nrnr
Schip1Schwannomin interacting protein 1[87]nrnrnr
Sdccag8Serologically defined colon cancer antigen 8[200]1613524Bardet-Biedl syndrome 16nr
Senior-Loken syndrome 7
Slc32a1/ViaatSolute carrier family 32, member 1[201,202]nrnrnr
Spry1Sprouty homolog 1[203]1602465nrnr
(Wnt1-Cre-mediated ablation)
Spry2Sprouty homolog 2[204]1602466nrnr
Sumo1SMT3 suppressor of mif two 3 homolog 1 (yeast)[205]1601912Orofacial cleft 10r
(heterozygous)
UgdhUDP-glucose dehydrogenase[206]1603370nrnr
(Wnt1-Cre-mediated ablation)
WdpcpWD repeat containing planar cell polarity effector[207]1613580ucnr
Extracellular proteins
Col2a1Collagen, type II, alpha 1[208]2120140Achondrogenesis, type IIr
Stickler syndrome, type I
Kniest dysplasia
Hspg2Heparan sulfate proteoglycan 2, perlecan[209,210]1142461Dyssegmental dysplasianr
Schwartz-Jampel syndrome, type 1
Serpinh1/Hsp47Serpine peptidase inhibitor, clade H, member 1[211]1600943Osteogenesis imperfecta, type Xnr
(Col2a1-Cre-mediated ablation)
Smoc1SPARC related modular calcium binding 1[212]1608488Microphthalmia with limb anomaliesr
Table 2 Classification of genes associated with cleft palate in mice.
Genes
Signaling pathway
TGF-beta signaling pathwayAcvr1/Alk2, Acvr2a, Bmp41, Bmp7, Bmpr1a/Alk3, Cdc42, Chrd, Crebbp/Cbp, Cited2, Foxc2/Mfh11, Foxd3, Foxe1/Titf2/Fkhl151, Foxf2, Fst, Inhba, Gdf11/Bmp11, Map3k7/Tak1, Pitx2, Smad4, Smad7, Tgfb21, Tgfb31, Tgfbr1/Alk51, Tgfbr21
Hedgehog signaling pathwayBmp41, Bmp7, Crebbp/Cbp, Gli21, Gli31, Gsk3b, Ptch1/Ptc11, Shh1, Smo/Smoh, Wnt5a1, Wnt9b
Wnt signaling pathwayAcvr1/Alk2, Ctnnb1, Crebbp/Cbp, Edn11, Fzd2, Gsk3b, Lrp6, Map3k7/Tak1, Prickle1, Smad4, Smo/Smoh, Wnt5a1, Wnt9b
FGF signaling pathwayFgf10, Fgf18, Fgf9, Fgfr11, Fgfr21, Grb2, Spry1, Spry2
MAPK signaling pathwayCdc42, Chuk/Ikk1/Tcf16, Egfr, Fgf10, Fgf18, Fgf9, Fgfr11, Fgfr21, Grb2, Map3k7/Tak1, Pdgfra1, Tgfb21, Tgfb31, Tgfbr1/Alk51, Tgfbr21, Crk, Itgb1
Cytokine-cytokine receptor interactionAcvr1/Alk2, Acvr2a, Bmp7, Bmpr1a/Alk3, Egfr, Inhba, Pdgfra1, Pdgfc1, Tgfb21, Tgfb31, Tgfbr1/Alk51, Tgfbr21, Vegfa
CBL mediated ligand- induced downregulation of EGF receptorsEgfr, Grb2, Pdgfra1
Sprouty regulation of tyrosine kinase signalsEgfr, Grb2, Spry2, Spry1
NFkB activationCrebbp/Cbp, Chuk/Ikk1/Tcf16, Map3k7/Tak1, Smad4, Tgfbr1/Alk51, Tgfbr21
Adherens junctionCrebbp/Cbp, Ctnnb1, Cdc42, Egfr, Fgfr11, Map3k7/ Tak1, Smad4, Snai2, Tgfbr1/Alk51, Tgfbr21
Focal adhesionCtnnb1, Cdc42, Col2a11, Crk, Egfr, Gsk3b, Grb2, Itga5, Itgb1, Itgb8, Ilk, Pdgfra1, Pdgfc1, Vegfa
Steroid biosynthesisCyp51, Dhcr71, Sc5d/Sc5dl
Cell cycleCrebbp/Cbp, Cdkn1c/p57kip21, Gsk3b, Smad4, Tgfb21, Tgfb31
Regulation of actin cytoskeletonCdc42, Crk, Egfr, Fgf9, Fgf10, Fgf18, Fgfr11, Fgfr21, Itga5, Itgb1, Itgb8, Pdgfra1, Pdgfc1
Axon guidanceCdc42, Efna5, Efnb11, Efnb2, Gsk3b, Itgb1
EndocytosisCdc42, Egfr, Fgfr21, Pdgfra1, Tgfbr1/Alk51, Tgfbr21
AngiogenesisCtnnb1, Crk, Efnb11, Efnb2, Fgfr11, Fgfr21, Fzd2, Gsk3b, Grb2, Jag1, Jag2, Pdgfra1, Pdgfc1, Vegfa, Wnt5a1
Family
Homeobox proteinAlx11, Barx1, Alx31, Alx41, Dlx1, Dlx2, Dlx51, Gbx2, Gsc, Hoxa21, Msx11, Msx21, Pax9, Prrx11, Pitx11, Pitx2, Rax, Shox2, Vax11
Tgf-beta receptor type I and IIAcvr1/Alk2, Acvr2a, Bmpr1a, Tgfbr1/Alk51, Tgfbr21
Tgf-beta familyBmp41, Bmp7, Gdf11, Inhba, Tgfb21, Tgfb31
Tyrosine protein kinaseEgfr, Fgfr11, Fgfr21, Pdgfra1, Ror21, Ryk
EphrinEfna5, Efnb11, Efnb2
Zinc finger proteinGli21, Gli31, Zic31, Hic1, Snai2
Forkhead proteinFoxc21, Foxd3, Foxe11, Foxf2
T-box proteinTbx11, Tbx2, Tbx221
Sox transcription factorSox5, Sox91, Sox11
Heparin-binding growth factor family member/FGFFgf9, Fgf10, Fgf18
SproutySpry1, Spry2
SmadSmad4, Smad7
Integrin beta subunitItgb1, Itgb8
FrizzledFzd2, Smo
Wnt relatedWnt5a1, Wnt9b
Serine-threonine protein kinaseIlk, Mpa3k7/Tak1
LIM domain containing proteinLhx81, Lhx7, Prickle1
EGF-like domain proteinJag1, Jag2
Figure 3
Figure 3 Gene ontology analysis of genes associated with cleft palate in mice. Gene ontology analysis of genes associated with cleft palate in mice was performed using the PANTHER classification system (http://pantherdb.org). The most significantly enriched molecular function was the “transcription factor” (P = 1.2 × 10-12). A P value less than 0.05 was considered statistically significant.

To analyze mutant mice with cleft palates, the defects in palatal shelf development were divided into the following six categories (Table 3), which were modified from a previously published classification[3]. The first category is the failure of the palatal shelf formation. The gene mutations affect the initial development of the palatal shelf. The second one is the abnormal fusion of the palatal shelves and the mandible or tongue. Oral fusions between the palatal shelves and the tongue or mandible are rare. In Tbx1 (T-box 1) knockout mice, the posterior part of the palatal shelves fuse to the mandible, inhibiting the elevation of the palatal shelves[4]. The third category is the failed or delayed palatal shelf elevation. Ablation of Pax9 (paired box gene 9), Pitx1 (paired-like homeodomain 1), Gli2 (GLI family zinc finger 2), or Osr2 (Odd-skipped related transcription factor 2) in the palatal mesenchyme results in the failed palatal shelf elevation[6-9], suggesting crucial roles for these transcription factors in controlling the mesenchymal cells during palatal shelf elevation. The fourth one is the failure of the palatal shelf development after elevation. The loss of Msx1 (msh homeobox 1) and Lhx8 (LIM homeobox gene 8) and the conditional ablation of Tgfbr2 (transforming growth factor, beta receptor II) in the neural crest or Shh (sonic hedgehog) in the epithelium result in failure of the palatal shelf development[10-13]. The fifth category is the persistence of medial edge epithelial (MEE) cells. The palatal epithelia are regionally divided into three parts: oral, nasal, and MEE. The MEE cells are removed from the fusion line by epithelial cell migration, apoptosis, and epithelial-mesenchymal transdifferentiation[14]. Tgfb3 (transforming growth factor, beta 3) or Egfr (epidermal growth factor receptor) knockout mice lack the adhesive interactions between the palatal shelves because the fate of MEE cells is altered[15-18]. In the last category, the cleft palate arises as a secondary defect, due to tongue or bone anomalies during development. For example, Hoxa2 (homeobox A2) knockout mice exhibit CP, because depression of the tongue is inhibited by the abnormal attachment of the hyoglossus muscle to the greater horn of the hyoid[19,20].

Table 3 Six categories of defects that result in cleft palate in mutant mice.
DefectsKnockout mice
(1)Failure of the palatal shelf formation (small palatal shelves)Acvr2a[34,50], 1Fgfr2[13], 1Lhx8[11], Pitx2[126], Itga5[65], Fst[46]
(2)Abnormal fusion of palatal shelves and tongue or the mandibleJag2[70], 1Irf6[109,110], 1Tbx1[4], Fgf10[41]
(3)Failure or delayed palatal shelf elevationPax9[6], 1Pitx1[7], 1Osr2[9], 1Gli2[8], 1Tgfb2[55], 1Pdgfc[51], Dhrs3[172]
(4)Failure of the palatal shelf development after the elevation1Msx1[10], 1Lhx8[11], 1Tgfbr2 (Wnt1-Cre-mediated ablation)[12]
(5)Persistence of medial edge epithelial cellsApaf1[158], 1Tgfb3[18], Egfr[17], Ctnnb1 (K14-Cre-mediated ablation)[166]
(6)Secondary defect1Hoxa2[19,20], 1Satb2[135], Acvr1/Alk2 (Wnt1-Cre-mediated ablation)[33]

There is molecular heterogeneity along the medial-lateral and anterior-posterior axes of palatal shelves. Regionally restricted expression of molecules provides distinct regulatory mechanisms for the development of palatal shelves. For instance, Msx1, Shox2 (short stature homeobox 2), Fgf10 (fibroblast growth factor 10), Bmp2 (bone morphogenetic protein 2), and Bmp4 (bone morphogenetic protein 4) are exclusively expressed in the anterior region of the palatal shelves[4,13,21,22]. The ablation of Msx1 in mice results in cell proliferation alterations in the anterior palatal mesenchyme and cleft palate[23]. Shox2 shows restricted expression patterns in the anterior palatal mesenchyme and the ablation of Shox2 in mice results in anterior cleft palates[22]. Fgf10 is also expressed in the anterior palatal mesenchymal cells and induces Shh expression through its receptor Fgfr2 (fibroblast growth factor receptor 2) in the palatal epithelium[13]. On the other hand, Pax9 is expressed in the posterior palatal shelves. Ablation of Pax9 results in cleft palates because of a palatal shelf development defect[6,21]. Even though it is known that Tbx1 induces the expression of Pax9 in the posterior part of palatal shelves[4], the mechanism of Tbx1-induced Pax9 expression during palatogenesis remains unknown. There is also molecular heterogeneity along the medial-lateral axis of the palatal shelf. For instance, Osr2 expression in the palatal shelf is characterized by a medial-lateral gradient. Loss of Osr2 results in the failure of palatal shelf elevation because of the delayed development of the medial part of palatal shelf[9].

MOLECULAR PATHOGENESIS OF CLEFT PALATES

Since most of the studies in mice focus on complete CP, the pathogenesis of other CP phenotypes is not well understood. Tbx1 is expressed in the developing palatal shelves in mice[4], highlighting the crucial function of Tbx1 in regulating palatal development. Loss of Tbx1 results in the abnormal fusion of the oral epithelia, which induces CP by preventing the elevation of palatal shelves[4]. The phenotypic variation in the Tbx1-/- palates strongly suggests that Tbx1 is involved in modifier genes and/or stochastic factors. Tgfb3-/- mice also exhibit either incomplete or complete CP[15,16]. Ablation of Shox2 results in anterior cleft palates[22]. Knockout mice of Sall3 (spalt-like transcription factor 3), which is expressed in the palatal mesenchyme, show hypoplasia of the soft palate and epiglottis[24]. These mice are unique models for studying the etiopathogenesis underlying the variety of CP phenotypes in humans.

A comprehensive list of molecules associated with CL/P in mice and their classification should provide insights into the genetic etiology of CL/P; however, the phenotype of knockout mice does not always recapitulate the phenotype in humans (Table 1). Since Table 1 includes the genes associated with tissue-specific conditional knockout mice, mutations of these genes may induce the phenotype of embryonic lethality in humans. Haploinsufficiency mutations of the TBX1 mutation are associated with CP[25]; however, heterozygous mice with Tbx1 are phenotypically normal, and Tbx1-/- mice have CP phenotypes[4], thereby suggesting a species-specific requirement for Tbx1 dosage. Mutations of the PVRL1 (poliovirus receptor-related 1 or Nectin 1) cause CL/P-ectodermal dysplasia syndrome and nonsyndromic CL/P (OMIM #225060), whereas Pvrl1-/- mice do not develop CP[26]. Lack of palatal phenotypes in mice may be a consequence of functional redundancy of Pvrl genes. Interestingly, Smad4, Smad7, Fgf9, Fgf10, and Fgf18 are involved in CP in mice (Table 1), whereas SMAD3 (OMIM *613795), FGF8 (OMIM *600483), and FGF17 (OMIM *603725) are involved in CP in humans.

Candidate genes for nonsyndromic CP in human must show a relevant spatio-temporal gene expression pattern in the developing palatal shelves, and induce a specific cleft palate phenotype when deleted[1]. Disease genes responsible for Mendelian forms of syndromic CP are also important in the etiology of nonsyndromic CP[27]. TBX1 mutations have been found in patients with incomplete CP without clinical diagnosis of del22q11.2 syndrome[25]. TBX1 is also one of the disease genes of conotruncal anomaly face syndrome (OMIM #217095), which is often associated with cleft palates, particularly submucosal CP, and bifid uvula. Tbx1-/- palatal phenotype in mice makes Tbx1 a potential candidate gene for nonsyndromic CP, especially submucosal CP and incomplete CP in humans.

RECENT ADVANCES IN PALATOGENESIS

Even though many genes associated with CP have been identified, little is known about how the environment influences gene expression in palatogenesis, and palatal phenotype. Epigenetics, such as DNA methylation and chromatin remodeling, and the microRNA (miRNA) regulation could change gene expression profiles and phenotypes. Hundreds of miRNAs, small non-coding RNAs that modulate gene expression at the post-transcriptional level are expressed in murine embryonic craniofacial tissue[28]. Conditional knockout mice of Dicer1 (dicer 1, ribonuclease type III), which regulates the generation of miRNA, resulted in disrupted palatogenesis[29], suggesting that the miRNA function may be important in mammalian palatogenesis. miR-140, which modulates BMP signaling, regulates palatogenesis in mice[30] and miR-17-92 modulates Tbx1 and Tbx3 (T-box 3) activity, resulting in orofacial clefting[31]. Interestingly, transcription of Dicer1 is regulated by TP63 (transformation related protein p63)[32], whose mutations are associated with cleft palate phenotypes (Table 1). Since genes involved in miRNA generation and individual CP genes can both be modulated by several miRNAs, it is conceivable that complex gene-miRNA interactions exist during palatogenesis. Genetically engineered mice with miRNAs, which modulate CP genes, may provide new information on the gene interactions underlying the palatogenesis. Further studies on miRNA and methylated genes involved in palatogenesis are necessary to understand the environmental factors contributing to CP.

CONCLUSION

Studies with genetically engineered mice with CP reveal the importance of regulated molecular functions in palatogenesis and provide the opportunity to discover new genes implicated in palatogenesis. However, there is still much to learn about transcriptional regulation and molecular networks in palatogenesis. The interactions between environmental/stochastic factors and genes in the etiopathogenesis of CL/P require further studies. Teratogenic effects of dioxins and retinoic acid have been reported in mice[1]. Mutant mice with CP can also be used as models to assess environmental effects or gene-environment interactions. Epithelial abnormal fusion could be one of the stochastic causes that induce a variety of CP phenotypes in mice. Understanding the palatal epithelial functions during palatogenesis may also lead to the discovery of novel therapeutic methods for CL/P.

Footnotes

P- Reviewer: Freire-De-Lima CG, Gokul S, Yeligar SM, Zhang L S- Editor: Ji FF L- Editor: A E- Editor: Wang CH

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