Molecular basis of cleft palates in mice

doi:10.4331/wjbc.v6.i3.121

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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
Processing time: 126 Days and 16.3 Hours

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.

Citation: Funato N, Nakamura M, Yanagisawa H. Molecular basis of cleft palates in mice. World J Biol Chem 2015; 6(3): 121-138
URL: https://www.wjgnet.com/1949-8454/full/v6/i3/121.htm
DOI: https://dx.doi.org/10.4331/wjbc.v6.i3.121

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).

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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].

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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/category	Protein	Ref.	OMIM	Syndrome	CL/P
Growth factors, antagonist, and receptors
Acvr1/Alk2	Activin A receptor, type I	[33]	¹102576	Fibrodysplasia ossificans progressiva	nr
(Wnt1-Cre-mediated ablation)	Activin A receptor, type I	[33]	¹102576	Fibrodysplasia ossificans progressiva	nr
Acvr2a	Activin A receptor, type IIA	[34]	¹102581	nr	nr
Bmp4	Bone morphogenetic protein 4	[35]	¹112262	Microphthalmia, syndromic 6	r
Bmp4	Bone morphogenetic protein 4	[35]	¹112262	Orofacial cleft 11	r
Bmp7	Bone morphogenetic protein 7	[36]	¹112267	nr	nr
Bmpr1a/Alk3	Bone morphogenetic protein receptor, type IA	[35]	¹601299	Juvenile polyposis syndrome,	nr
(Nestin-Cre-mediated ablation)	Bone morphogenetic protein receptor, type IA	[35]	¹601299	Polyposis syndrome	nr
Chrd	Chordin	[37]	¹603475	nr	nr
Ctgf	Connective tissue growth factor	[38]	¹121009	nr	nr
Edn1	Endothelin 1	[39]	²131240	Auriculocondylar syndrome 3	r
Egfr	Epidermal growth factor receptor	[17]	¹131550	nr	nr
Fgf9	Fibroblast growth factor 9	[40]	¹600921	uc	nr
Fgf10	Fibroblast growth factor 10	[13,41]	¹602115	Aplasia of lacrimal and salivary glands	nr
Fgf10	Fibroblast growth factor 10	[13,41]	¹602115	LADD syndrome	nr
Fgf18	Fibroblast growth factor 18	[42,43]	¹603726	nr	nr
Fgfr1	Fibroblast growth factor receptor 1	[44]	¹136350	Nonsyndromic cleft lip/palate	r
				Hartsfield syndrome
				Hypogonadotropic hypogonadism 2
				Pfeiffer syndrome
Fgfr2	Fibroblast growth factor receptor 2	[13,45]	¹176943	Apert syndrome	r
(knockout) (Krt14-Cre-mediated ablation)				Crouzon syndrome
				Pfeiffer syndrome
				Saethre-Chotzen syndrome
Fst	Follistatin	[46]	¹136470	nr	nr
Gabrb3	Gamma-aminobutyric acid A receptor, beta 3	[47]	¹137192	Epilepsy, childhood absence, susceptibility to, 5	r
Gdf11/Bmp11	Growth differentiation factor 11	[48]	¹603936	nr	nr
Gpr124	G protein-coupled receptor 124	[49]	¹606823	nr	nr
Inhba	Inhibin, beta A/activin A	[50]	¹147290	nr	nr
Pdgfc	Platelet-derived growth factor C	[51]	¹608452	nr	r [52]
Pdgfra	Platelet-derived growth factor receptor, alpha polypeptide	[53,54]	¹173490	Gastrointestinal stromal tumor, somatic	r
(knockout) (Wnt1-Cre-mediated ablation)	Platelet-derived growth factor receptor, alpha polypeptide	[53,54]	¹173490	Hypereosinophilic syndrome, idiopathic, resistant to imatinib	r
Tgfb2	Transforming growth factor, beta 2	[55]	¹190220	Loeys-Dietz syndrome, type 4	r
Tgfb3	Transforming growth factor, beta 3	[15,16,18]	¹190230	Arrhythmogenic right ventricular dysplasia 1	r
Tgfbr1/Alk5	Transforming growth factor, beta receptor I	[56,57]	¹190181	Loeys-Dietz syndrome, type 1	r
(Wnt1-Cre-, and Nestin-Cre-mediated ablation)	Transforming growth factor, beta receptor I	[56,57]	¹190181	Loeys-Dietz syndrome, type 1	r
Tgfbr2	Transforming growth factor, beta receptor II	[12,58]	¹190182	Loeys-Dietz syndrome, type 2	r
(Wnt1-Cre-, and KRT14-Cre-mediated ablation)	Transforming growth factor, beta receptor II	[12,58]	¹190182	Loeys-Dietz syndrome, type 2	r
Vegfa	Vascular endothelial growth factor A	[59]	²192240	nr	nr
Membrane proteins
Ceacam1	Carcinoembryonic antigen-related cell adhesion molecule 1	[60]	¹109770	nr	nr
Efna5	Ephrin A5	[61]	¹601535	nr	nr
Efnb1	Ephrin B1	[62]	¹300035	Craniofrontonasal dysplasia	r
Efnb2	Ephrin B2	[63]	¹600527	nr	nr
Fzd2	Frizzled class receptor 2	[64]	¹600667	nr	nr
Itga5	Integrin alpha 5	[65,66]	¹135620	nr	nr
(knockout) (Mesp1-Cre-mediated ablation)	Integrin alpha 5	[65,66]	¹135620	nr	nr
Itgb1	Integrin beta 1	[67]	¹135630	nr	nr
(Col2a1-Cre-mediated ablation)	Integrin beta 1	[67]	¹135630	nr	nr
Itgb8	Integrin beta 8	[68]	¹604160	nr	nr
Jag1	Jagged1	[69]	²601920	Alagille syndrome	nr
(Wnt1-Cre-mediated ablation)	Jagged1	[69]	²601920	Alagille syndrome	nr
Jag2	Jagged2	[70]	¹602570	nr	nr
Kcnj2	Potassium inwardly-rectifying channel, subfamily J, member 2	[71]	¹600681	Andersen syndrome	r
				Atrial fibrillation, familial, 9
				Short QT syndrome 3
Lrp6	Low density lipoprotein receptor-related protein 6	[72]	¹603507	nr	nr
Ror2	Receptor tyrosine kinase-like orphan receptor 2	[73]	¹602337	Robinow syndrome, autosomal recessive	r
Ror2	Receptor tyrosine kinase-like orphan receptor 2	[73]	¹602337	Brachydactyly, type B1	r
Ryk	Receptor-like tyrosine kinase	[74]	¹600524	nr	nr
Ryr1	Ryanodine receptor 1, skeletal muscle	[75]	¹180901	Central core disease	nr
				King-Denborough syndrome
				Minicore myopathy with external ophthalmoplegia
Sc5d/Sc5dl	Sterol-C5-desaturase (fungal ERG3, delta-5-desaturase) homolog (S. cerevisae)	[76]	¹602286	Lathosterolosis	nr
Shh	Sonic hedgehog	[13,77]	¹600725	Holoprosencephaly-3	r
(KRT14-Cre-, and Sox2-Cre-mediated ablation)				Microphthalmia with coloboma 5
(KRT14-Cre-, and Sox2-Cre-mediated ablation)				Single median maxillary central incisor
Smo/Smoh	Smoothened, frizzled class receptor	[78]	¹601500	Basal cell carcinoma, somatic	nr
(Wnt1-Cre-mediated ablation)	Smoothened, frizzled class receptor	[78]	¹601500	Basal cell carcinoma, somatic	nr
Tctn2	Tectonic family member 2	[79]	¹613846	Meckel syndrome 8	r
Wls/Gpr177	Wntless homolog (Drosophila)	[80]	¹611514	nr	nr
(Wnt1-Cre-mediated ablation)	Wntless homolog (Drosophila)	[80]	¹611514	nr	nr
Wnt5a	Wingless-type MMTV integration site family, member 5A	[81]	¹164975	Robinow syndrome, autosomal dominant	r
Wnt9b	Wingless-type MMTV integration site family, member 9B	[82,83]	¹602864	nr	nr
(knockout) (Foxg1-Cre-mediated ablation)	Wingless-type MMTV integration site family, member 9B	[82,83]	¹602864	nr	nr
Transcription and nucleolar factors
Alx1	Aristaless-like homeobox 1	[84]	¹601527	Frontonasal dysplasia 3	r
Alx3	Aristaless-like homeobox 3	[85]	¹606014	Frontonasal dysplasia 1	r
Alx4	Aristaless-like homeobox 4	[85]	¹605420	Frontonasal dysplasia 2	Cleft alae nasi
				Parietal foramina 2
				Craniosynostosis 5
Anp32b	Acidic (leucine-rich) nuclear phosphoprotein 32 family, member B	[86]	nr	nr	nr
Arid5	AT-rich interaction domain-containing protein 5A	[87]	¹611583	nr	nr
Asxl1	Additional sex combs like 1	[88]	¹612990	Bohring-Opitz syndrome	r
Asxl1	Additional sex combs like 1	[88]	¹612990	Myelodysplastic syndrome, somatic	r
Barx1	BarH-like homeobox 1	[89]	¹603260	nr	nr
Cdc42	Cell division cycle 42	[90]	¹116952	nr	nr
(Prrx1-Cre-mediated ablation)	Cell division cycle 42	[90]	¹116952	nr	nr
Chd7	Chromodomain helicase DNA binding protein 7	[91,92]	¹608892	CHARGE syndrome	r
(heterozygotes) (Wnt1-Cre-mediated ablation)	Chromodomain helicase DNA binding protein 7	[91,92]	¹608892	Hypogonadotropic hypogonadism 5 with or without anosmia	r
Cited2	CBP/p300-interacting transactivator, with Glu/Asp-rich C-terminal domain, 2	[93]	¹602937	Atrial septal defect 8	nr
Cited2		[93]	¹602937	Ventricular septal defect 2	nr
Crebbp/Cbp	CREB binding protein	[94]	¹600140	Rubinstein-Taybi syndrome	nr
Dlx1	Distal-less homeobox 1	[95]	¹600029	nr	nr
Dlx2	Distal-less homeobox 2	[95]	¹126255	nr	nr
Dlx5	Distal-less homeobox 5	[96,97]	¹600028	Split-hand/foot malformation 1 with sensorineural hearing loss	r
Dph1/Ovca1	DPH1 homolog (S. cerevisiae)	[98]	¹603527	nr	nr
Eya1	Eyes absent 1 homolog (Drosophila)	[99]	¹601653	Branchiootic syndrome 1	r
				Branchiootorenal syndrome 1, with or without cataracts
				Anterior segment anomalies with or without cataract
Foxc2/Mfh1	Forkhead box C2	[100]	¹602402	Lymphedema-distichiasis syndrome	r
Foxd3	Forkhead box D3	[101]	¹611539	uc	nr
(Wnt1-Cre-mediated ablation)	Forkhead box D3	[101]	¹611539	uc	nr
Foxe1/Titf2/Fkhl15	Forkhead box E1	[102]	¹602617	Bamforth-Lazarus syndrome	r
Foxe1/Titf2/Fkhl15	Forkhead box E1	[102]	¹602617	Nonsyndromic orofacial clefting	r
Foxf2	Forkhead box F2	[103]	¹603250	nr	nr
Gbx2	Gastrulation brain homeobox 2	[104]	¹601135	nr	nr
Gli2	GLI family zinc finger 2	[8]	¹165230	Culler-Jones syndrome	r
Gli2	GLI family zinc finger 2	[8]	¹165230	Holoprosencephaly-9	r
Gli3	GLI family zinc finger 3	[105]	¹165240	Greig cephalopolysyndactyly syndrome	r
Gli3	GLI family zinc finger 3	[105]	¹165240	Pallister-Hall syndrome	r
Gsc	Goosecoid homeobox	[106]	¹138890	Short stature, auditory canal atresia, mandibular hypoplasia, skeletal abnormalities	nr
Hand2/dHand	Heart and neural crest derivatives expressed 2	[107]	¹602407	nr	nr
Hic1	Hypermethylated in cancer 1	[108]	¹603825	nr	nr
Hoxa2	Homeobox A2	[19]	¹604685	Microtia with or without hearing impairment (AD)	r
Hoxa2	Homeobox A2	[19]	¹604685	Microtia, hearing impairment, and cleft palate (AR)	r
Irf6	Interferon regulatory factor 6	[109,110]	¹607199	van der Woude syndrome	r
				Orofacial cleft 6
				Popliteal pterygium syndrome 1
Jmjd6/Ptdsr	Jumonji domain containing 6	[111]	¹604914	nr	nr
Kat6a/Moz/Myst3	K (lysine) Acetyltransferase 6A	[112]	¹601408	nr	nr
Lhx7	LIM homeobox gene 7	[113]	nr	nr	nr
Lhx8	LIM homeobox gene 8	[11]	¹604425	nr	r
Luzp1	Leucine zipper protein 1	[114]	¹601422	nr	nr
Mef2c	MADS box transcription enhancer factor 2	[115]	¹600662	Chromosome 5q14.3 deletion syndrome	nr
(Wnt1-Cre-mediated ablation)	MADS box transcription enhancer factor 2	[115]	¹600662	Mental retardation, stereotypic movements, epilepsy, and/or cerebral malformations	nr
Meox2	Mesenchyme homeobox 2	[116]	¹600535	nr	nr
Mn1	Meningioma 1	[117]	¹156100	Meningioma	nr
Mnt	Max binding protein	[118]	¹603039	nr	nr
Msx1	Msh homeobox 1	[10,23]	¹142983	Ectodermal dysplasia 3, Witkop type	r
				Orofacial cleft 5
				Tooth agenesis, selective, 1, with or without orofacial cleft
Msx2	Msh homeobox 2	[119]	¹123101	Craniosynostosis, type 2	r
(missense mutation)				Parietal foramina 1
(missense mutation)				Parietal foramina with cleidocranial dysplasia
Nabp2/Obfc2b/hSSB1	Nucleic acid binding protein 2	[120,121]	¹612104	nr	nr
Osr2	Odd-skipped related transcription factor 2	[9]	¹611297	nr	r
Pak1ip1	PAK1 interacting protein 1	[122]	¹607811	nr	nr
Pax9	Paired box gene 9	[6]	¹167416	Tooth agenesis, selective, 3	nr
Pbx1	Pre B cell leukemia homeobox 1	[83]	¹176310	Leukemia, acute pre-B-cell	nr
Pds5a	PDS5, regulator of cohesion maintenance, homolog A (S. cerevisiae)	[123]	¹613200	nr	nr
Phc1/Rae28	Polyhomeotic homolog 1	[124]	¹602978	uc	nr
Pitx1	Paired-like homeodomain 1	[7,125]	¹602149	Clubfoot, congenital, with or without deficiency of long bones and/or mirror-image polydactyly	r
Pitx1	Paired-like homeodomain 1	[7,125]	¹602149	Liebenberg syndrome	r
Pitx2	Paired-like homeodomain 2	[126]	¹601542	Axenfeld-Rieger syndrome, type 1	nr
				Iridogoniodysgenesis, type 2
				Peters anomaly
Pnn	Pinin	[127]	¹603154	nr	nr
Prdm16	PR domain containing 16	[128]	¹605557	Cardiomyopathy, dilated, 1LL	nr
Prdm16	PR domain containing 16	[128]	¹605557	Left ventricular noncompaction 8	nr
Prrx1/Prx1/Mhox	Paired related homeobox 1	[129]	¹167420	Agnathia-otocephaly complex	r
Ptch1/Ptc1	Patched 1	[130]	¹601309	Basal cell nevus syndrome	r
(Wnt1-Cre-mediated ablation)				(Gorlin syndrome)
(Wnt1-Cre-mediated ablation)				Holoprosencephaly type 7
Pygo2	Pygopus 2	[131]	¹606903	nr	nr
(CMV-Cre-mediated ablation)	Pygopus 2	[131]	¹606903	nr	nr
Rax	Retina and anterior neural fold homeobox	[132]	¹601881	Microphthalmia, isolated 3	nr
Recql4	RecQ protein-like 4	[133]	¹603780	Baller-Gerold syndrome	r
				RAPADILINO syndrome
				Rothmund-Thomson syndrome
Runx2	Runt-related transcription factor 2	[134]	¹600211	Cleidocranial dysplasia	r
Sall3	Spalt-like transcription factor 3	[24]	¹605079	nr	nr
Satb2	SATB homeobox 2	[135,136]	¹608148	Glass syndrome	r
Shox2	Short stature homeobox 2	[22]	¹602504	nr	nr
Sim2	Single-minded family bHLH transcription factor 2	[137]	¹600892	nr	nr
Smad4 (Osr2-Cre-mediated ablation)	SMAD family member 4	[138]	¹600993	Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome	nr
Smad4 (Osr2-Cre-mediated ablation)	SMAD family member 4	[138]	¹600993	Myhre syndrome	nr
Smad7	SMAD family member 7	[139]	¹602932	uc	nr
Snai2	Snail family zinc finger 2	[140]	¹602150	Piebaldism	nr
Snai2	Snail family zinc finger 2	[140]	¹602150	Waardenburg syndrome, type 2D	nr
Sox5	SRY (sex determining region Y)-box 5	[141]	¹604975	nr	nr
Sox9 (heterozygous)	SRY (sex determining region Y)-box 9	[142,143]	¹608160	Acampomelic campomelic dysplasia	r
(Wnt1-Cre-mediated ablation)	SRY (sex determining region Y)-box 9	[142,143]	¹608160	Acampomelic campomelic dysplasia	r
Sox11	SRY (sex determining region Y)-box 11	[144]	¹600898	Mental retardation, autosomal dominant, 27	nr
Sp8	Sp8 transcription factor	[145]	¹608306	nr	nr
Tshz1	Teashirt zinc finger family member 1	[146]	¹614427	Aural atresia, congenital	nr
Tbx1	T-box 1	[4,147]	¹602054	DiGeorge syndrome	r
(knockout) (KRT14-Cre-mediated ablation)				Velocardiofacial syndrome
				Conotruncal anomaly face syndrome
				Tetralogy of Fallot
Tbx2	T-box 2	[148]	¹600747	nr	nr
Tbx22	T-box 22	[149]	¹300307	Cleft palate with ankyloglossia	r
Tbx22	T-box 22	[149]	¹300307	submucous cleft palate (SMCP)	r
Tcof1	Treacher Collins-Franceschetti syndrome 1	[150]	¹606847	Treacher-Collins syndrome	r
(heterozygous)	Treacher Collins-Franceschetti syndrome 1	[150]	¹606847	Treacher-Collins syndrome	r
Tfap2A	Transcription factor AP-2 alpha	[151]	¹107580	Branchio-oculo-facial syndrome	r
(Wnt1-Cre-mediated ablation)	Transcription factor AP-2 alpha	[151]	¹107580	Branchio-oculo-facial syndrome	r
Trp63/Tp63	Transformation related protein p63	[152]	¹603273	Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3	r
				Orofacial cleft 8
				Hay-Wells syndrome
				Limb-mammary syndrome
Vax1	Ventral anterior homeobox 1	[153]	¹604294	Microphthalmia, syndromic 11	r
Whsc1	Wolf-Hirschhorn syndrome candidate 1	[154]	¹602952	nr	nr
Zeb1	Zinc finger E-box binding homeobox 1	[155]	¹189909	Corneal dystrophy	nr
Zfp640/Mzf6d	Zinc finger protein 640	[87]	nr	nr	nr
Zic3	Zinc finger protein of the cerebellum 3	[156]	¹300265	Congenital heart defects, nonsyndromic	r
				Heterotaxy, visceral, 1
				VACTERL association
Cytoplasmic proteins
Akap8/Akap95	A kinase (PRKA) anchor protein 8	[157]	¹604692	nr	nr
Apaf1	Apoptotic peptidase activating factor 1	[158]	¹602233	nr	nr
B9d1	B9 protein domain 1	[159]	¹614144	Meckel syndrome 9	nr
Cask	Calcium/calmodulin-dependent serine protein kinase	[160]	¹300172	FG syndrome 4	r
Cask	Calcium/calmodulin-dependent serine protein kinase	[160]	¹300172	Mental retardation and microcephaly with pontine and cerebellar hypoplasia	r
Cdkn1c/p57kip2	Cyclin-dependent kinase inhibitor 1C	[161,162]	¹600856	Beckwith-Wiedemann syndrome	r
Cdkn1c/p57kip2	Cyclin-dependent kinase inhibitor 1C	[161,162]	¹600856	IMAGe syndrome	r
Chuk/Ikk1/Tcf16	Conserved helix-loop-helix ubiquitous kinase	[163]	¹600664	Cocoon syndrome	nr
Crk	v-crk sarcoma virus CT10 oncogene homolog	[164]	¹164762	nr	nr
Ctnnb1	Catenin (cadherin-associated protein), beta 1,	[165,166]	¹116806	Mental retardation, autosomal dominant 19	nr
(KRT14-Cre-mediated ablation)	Catenin (cadherin-associated protein), beta 1,	[165,166]	¹116806	Mental retardation, autosomal dominant 19	nr
Cyp26B1	Cytochrome P450, family 26, subfamily b, polypeptide 1	[167]	¹605207	Craniosynostosis with radiohumeral fusions and other skeletal and craniofacial anomalies	nr
Cyp51	Cytochrome P450, family 51	[168]	¹601637	nr	nr
Dhcr7	7-dehydrocholesterol reductase	[169,170]	¹602858	Smith-Lemli-Opitz syndrome	r
Dhrs3	Dehydrogenase/reductase (SDR family) member 3	[171,172]	¹612830	nr	nr
Dicer1	Dicer 1, ribonuclease type III	[29]	¹606241	Rhabdomyosarcoma, embryonal, 2	nr
(Pax2-Cre-mediated ablation)				Goiter, multinodular 1
(Pax2-Cre-mediated ablation)				Pleuropulmonary blastoma
Dlg1/Dlgh/Sap97	Discs large 1	[173]	¹601014	nr	nr
Fuz	Fuzzy planar cell polarity protein	[174]	¹610622	Neural tube defects	nr
Gab1	Growth factor receptor bound protein 2-associated protein 1	[175]	¹604439	nr	nr
Gad1/Gad67	Glutamate decarboxylase 1	[176,177]	¹605363	Cerebral palsy, spastic quadriplegic, 1	r
Glce	Glucuronyl C5-epimerase	[178]	¹612134	nr	nr
Glg1	Golgi apparatus protein 1	[179]	¹600753	nr	nr
Grb2	Growth factor receptor bound protein 2	[180]	¹108355	nr	nr
Gsk3b	Glycogen synthase kinase 3 beta	[181]	¹605004	nr	nr
Hs2st1	Heparan sulfate 2-O-sulfotransferase 1	[182]	¹604844	nr	nr
Hspb11/Ift25	Heat shock protein family B (small), member 11	[183]	¹604844	nr	nr
Ilk	Integrin linked kinase	[184]	¹602366	nr	nr
(Col2a1-Cre-mediated ablation)	Integrin linked kinase	[184]	¹602366	nr	nr
Impad1/Jaws	Inositol monophosphatase domain containing 1	[185]	¹614010	Chondrodysplasia with joint dislocations, GRAPP type	r
Inpp5e	Inositol polyphosphate-5-phosphatase E	[186]	¹613037	Joubert syndrome 1	nr
Inpp5e	Inositol polyphosphate-5-phosphatase E	[186]	¹613037	Mental retardation, truncal obesity, retinal dystrophy, and micropenis	nr
Kif3a	Kinesin family member 3A	[187]	¹604683	nr	nr
(Wnt1-Cre-mediated ablation)	Kinesin family member 3A	[187]	¹604683	nr	nr
Map3k7/Tak1	Mitogen-activated protein kinase kinase kinase 7	[188,189]	¹602614	nr	nr
(Wnt1-Cre-mediated ablation)	Mitogen-activated protein kinase kinase kinase 7	[188,189]	¹602614	nr	nr
Nprl3	Nitrogen permease regulator-like 3	[190]	¹600928	nr	nr
Ofd1	Oral-facial-digital syndrome 1 gene homolog (human)	[191]	¹300170	Joubert syndrome 10	r
(CAG-Cre-mediated ablation)				Orofaciodigital syndrome I
(CAG-Cre-mediated ablation)				Simpson-Golabi-Behmel syndrome, type 2
Pdss2	Prenyl (solanesyl) diphosphate synthase, subunit 2	[192]	¹610564	Coenzyme Q10 deficiency, primary, 3	nr
(Pax2-Cre-mediated ablation)	Prenyl (solanesyl) diphosphate synthase, subunit 2	[192]	¹610564	Coenzyme Q10 deficiency, primary, 3	nr
Piga	Phosphatidylinositol glycan anchor biosynthesis, class A	[193]	¹311770	Multiple congenital anomalies-hypotonia-seizures syndrome 2 Paroxysmal nocturnal hemoglobinuria, somatic	nr
(EIIa-Cre-mediated ablation)	Phosphatidylinositol glycan anchor biosynthesis, class A	[193]	¹311770		nr
Pkdcc/Vlk	Protein kinase domain containing, cytoplasmic	[194,195]	¹614150	nr	nr
(Sox2-Cre-mediated ablation)	Protein kinase domain containing, cytoplasmic	[194,195]	¹614150	nr	nr
Prickle1	Prickle homolog 1	[196]	¹608500	Epilepsy, progressive myoclonic 1B	nr
Rad23b	RAD23b homolog (S. cerevisiae)	[197]	¹600062	nr	nr
Rspo2	R-spondin 2 homolog (Xenopus laevis)	[198,199]	¹610575	nr	nr
Schip1	Schwannomin interacting protein 1	[87]	nr	nr	nr
Sdccag8	Serologically defined colon cancer antigen 8	[200]	¹613524	Bardet-Biedl syndrome 16	nr
Sdccag8	Serologically defined colon cancer antigen 8	[200]	¹613524	Senior-Loken syndrome 7	nr
Slc32a1/Viaat	Solute carrier family 32, member 1	[201,202]	nr	nr	nr
Spry1	Sprouty homolog 1	[203]	¹602465	nr	nr
(Wnt1-Cre-mediated ablation)	Sprouty homolog 1	[203]	¹602465	nr	nr
Spry2	Sprouty homolog 2	[204]	¹602466	nr	nr
Sumo1	SMT3 suppressor of mif two 3 homolog 1 (yeast)	[205]	¹601912	Orofacial cleft 10	r
(heterozygous)	SMT3 suppressor of mif two 3 homolog 1 (yeast)	[205]	¹601912	Orofacial cleft 10	r
Ugdh	UDP-glucose dehydrogenase	[206]	¹603370	nr	nr
(Wnt1-Cre-mediated ablation)	UDP-glucose dehydrogenase	[206]	¹603370	nr	nr
Wdpcp	WD repeat containing planar cell polarity effector	[207]	¹613580	uc	nr
Extracellular proteins
Col2a1	Collagen, type II, alpha 1	[208]	²120140	Achondrogenesis, type II	r
				Stickler syndrome, type I
				Kniest dysplasia
Hspg2	Heparan sulfate proteoglycan 2, perlecan	[209,210]	¹142461	Dyssegmental dysplasia	nr
Hspg2	Heparan sulfate proteoglycan 2, perlecan	[209,210]	¹142461	Schwartz-Jampel syndrome, type 1	nr
Serpinh1/Hsp47	Serpine peptidase inhibitor, clade H, member 1	[211]	¹600943	Osteogenesis imperfecta, type X	nr
(Col2a1-Cre-mediated ablation)	Serpine peptidase inhibitor, clade H, member 1	[211]	¹600943	Osteogenesis imperfecta, type X	nr
Smoc1	SPARC related modular calcium binding 1	[212]	¹608488	Microphthalmia with limb anomalies	r

¹Before an OMIM entry number indicates a gene;

²Before an OMIM entry number indicates that the entry includes a description of a gene of known sequence and a phenotype. OMIM: Online Mendelian Inheritance in Man (http://omim.org); CL/P: Cleft lip and/or palate; r: Reported; nr: Not reported; uc: Unclarified.

Table 2 Classification of genes associated with cleft palate in mice.

	Genes
Signaling pathway
TGF-beta signaling pathway	Acvr1/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 pathway	Bmp4¹, Bmp7, Crebbp/Cbp, Gli2¹, Gli3¹, Gsk3b, Ptch1/Ptc1¹, Shh¹, Smo/Smoh, Wnt5a¹, Wnt9b
Wnt signaling pathway	Acvr1/Alk2, Ctnnb1, Crebbp/Cbp, Edn1¹, Fzd2, Gsk3b, Lrp6, Map3k7/Tak1, Prickle1, Smad4, Smo/Smoh, Wnt5a¹, Wnt9b
FGF signaling pathway	Fgf10, Fgf18, Fgf9, Fgfr1¹, Fgfr2¹, Grb2, Spry1, Spry2
MAPK signaling pathway	Cdc42, Chuk/Ikk1/Tcf16, Egfr, Fgf10, Fgf18, Fgf9, Fgfr1¹, Fgfr2¹, Grb2, Map3k7/Tak1, Pdgfra¹, Tgfb2¹, Tgfb3¹, Tgfbr1/Alk5¹, Tgfbr2¹, Crk, Itgb1
Cytokine-cytokine receptor interaction	Acvr1/Alk2, Acvr2a, Bmp7, Bmpr1a/Alk3, Egfr, Inhba, Pdgfra¹, Pdgfc¹, Tgfb2¹, Tgfb3¹, Tgfbr1/Alk5¹, Tgfbr2¹, Vegfa
CBL mediated ligand- induced downregulation of EGF receptors	Egfr, Grb2, Pdgfra¹
Sprouty regulation of tyrosine kinase signals	Egfr, Grb2, Spry2, Spry1
NFkB activation	Crebbp/Cbp, Chuk/Ikk1/Tcf16, Map3k7/Tak1, Smad4, Tgfbr1/Alk5¹, Tgfbr2¹
Adherens junction	Crebbp/Cbp, Ctnnb1, Cdc42, Egfr, Fgfr1¹, Map3k7/ Tak1, Smad4, Snai2, Tgfbr1/Alk5¹, Tgfbr2¹
Focal adhesion	Ctnnb1, Cdc42, Col2a1¹, Crk, Egfr, Gsk3b, Grb2, Itga5, Itgb1, Itgb8, Ilk, Pdgfra¹, Pdgfc¹, Vegfa
Steroid biosynthesis	Cyp51, Dhcr7¹, Sc5d/Sc5dl
Cell cycle	Crebbp/Cbp, Cdkn1c/p57kip2¹, Gsk3b, Smad4, Tgfb2¹, Tgfb3¹
Regulation of actin cytoskeleton	Cdc42, Crk, Egfr, Fgf9, Fgf10, Fgf18, Fgfr1¹, Fgfr2¹, Itga5, Itgb1, Itgb8, Pdgfra¹, Pdgfc¹
Axon guidance	Cdc42, Efna5, Efnb1¹, Efnb2, Gsk3b, Itgb1
Endocytosis	Cdc42, Egfr, Fgfr2¹, Pdgfra¹, Tgfbr1/Alk5¹, Tgfbr2¹
Angiogenesis	Ctnnb1, Crk, Efnb1¹, Efnb2, Fgfr1¹, Fgfr2¹, Fzd2, Gsk3b, Grb2, Jag1, Jag2, Pdgfra¹, Pdgfc¹, Vegfa, Wnt5a¹
Family
Homeobox protein	Alx1¹, Barx1, Alx3¹, Alx4¹, Dlx1, Dlx2, Dlx5¹, Gbx2, Gsc, Hoxa2¹, Msx1¹, Msx2¹, Pax9, Prrx1¹, Pitx1¹, Pitx2, Rax, Shox2, Vax1¹
Tgf-beta receptor type I and II	Acvr1/Alk2, Acvr2a, Bmpr1a, Tgfbr1/Alk5¹, Tgfbr2¹
Tgf-beta family	Bmp4¹, Bmp7, Gdf11, Inhba, Tgfb2¹, Tgfb3¹
Tyrosine protein kinase	Egfr, Fgfr1¹, Fgfr2¹, Pdgfra¹, Ror2¹, Ryk
Ephrin	Efna5, Efnb1¹, Efnb2
Zinc finger protein	Gli2¹, Gli3¹, Zic3¹, Hic1, Snai2
Forkhead protein	Foxc2¹, Foxd3, Foxe1¹, Foxf2
T-box protein	Tbx1¹, Tbx2, Tbx22¹
Sox transcription factor	Sox5, Sox9¹, Sox11
Heparin-binding growth factor family member/FGF	Fgf9, Fgf10, Fgf18
Sprouty	Spry1, Spry2
Smad	Smad4, Smad7
Integrin beta subunit	Itgb1, Itgb8
Frizzled	Fzd2, Smo
Wnt related	Wnt5a¹, Wnt9b
Serine-threonine protein kinase	Ilk, Mpa3k7/Tak1
LIM domain containing protein	Lhx8¹, Lhx7, Prickle1
EGF-like domain protein	Jag1, Jag2

¹Genes involved in human cleft lip and/or palate. TGF: Transforming growth factor; FGF: Fibroblast growth factor; MAPK: Mitogen-activated protein kinase; CBL: Casitas B-lineage lymphoma; EGF: Epidermal growth factor.

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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.

	Defects	Knockout 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 mandible	Jag2[70], ¹Irf6[109,110], ¹Tbx1[4], Fgf10[41]
(3)	Failure or delayed palatal shelf elevation	Pax9[6], ¹Pitx1[7], ¹Osr2[9], ¹Gli2[8], ¹Tgfb2[55], ¹Pdgfc[51], Dhrs3[172]
(4)	Failure of the palatal shelf development after the elevation	¹Msx1[10], ¹Lhx8[11], ¹Tgfbr2 (Wnt1-Cre-mediated ablation)[12]
(5)	Persistence of medial edge epithelial cells	Apaf1[158], ¹Tgfb3[18], Egfr[17], Ctnnb1 (K14-Cre-mediated ablation)[166]
(6)	Secondary defect	¹Hoxa2[19,20], ¹Satb2[135], Acvr1/Alk2 (Wnt1-Cre-mediated ablation)[33]

¹Genes involved in human cleft lip and/or palate.

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

References

1.	Murray JC. Gene/environment causes of cleft lip and/or palate. Clin Genet. 2002;61:248-256. [PubMed] [DOI] [Cited in This Article: ]

2.	Jones MC. Etiology of facial clefts: prospective evaluation of 428 patients. Cleft Palate J. 1988;25:16-20. [PubMed] [DOI] [Cited in This Article: ]

3.	Chai Y, Maxson RE. Recent advances in craniofacial morphogenesis. Dev Dyn. 2006;235:2353-2375. [PubMed] [DOI] [Cited in This Article: ]

Funato N, Nakamura M, Richardson JA, Srivastava D, Yanagisawa H. Tbx1 regulates oral epithelial adhesion and palatal development. Hum Mol Genet. 2012;21:2524-2537. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 43] [Cited by in F6Publishing: 44] [Article Influence: 3.7] [Reference Citation Analysis (0)]

Mi H, Muruganujan A, Thomas PD. PANTHER in 2013: modeling the evolution of gene function, and other gene attributes, in the context of phylogenetic trees. Nucleic Acids Res. 2013;41:D377-D386. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 1196] [Cited by in F6Publishing: 1288] [Article Influence: 107.3] [Reference Citation Analysis (0)]

6.	Peters H, Neubüser A, Kratochwil K, Balling R. Pax9-deficient mice lack pharyngeal pouch derivatives and teeth and exhibit craniofacial and limb abnormalities. Genes Dev. 1998;12:2735-2747. [PubMed] [DOI] [Cited in This Article: ]

Szeto DP, Rodriguez-Esteban C, Ryan AK, O’Connell SM, Liu F, Kioussi C, Gleiberman AS, Izpisúa-Belmonte JC, Rosenfeld MG. Role of the Bicoid-related homeodomain factor Pitx1 in specifying hindlimb morphogenesis and pituitary development. Genes Dev. 1999;13:484-494. [PubMed] [Cited in This Article: ]

8.	Mo R, Freer AM, Zinyk DL, Crackower MA, Michaud J, Heng HH, Chik KW, Shi XM, Tsui LC, Cheng SH. Specific and redundant functions of Gli2 and Gli3 zinc finger genes in skeletal patterning and development. Development. 1997;124:113-123. [PubMed] [DOI] [Cited in This Article: ]

9.	Lan Y, Ovitt CE, Cho ES, Maltby KM, Wang Q, Jiang R. Odd-skipped related 2 (Osr2) encodes a key intrinsic regulator of secondary palate growth and morphogenesis. Development. 2004;131:3207-3216. [PubMed] [DOI] [Cited in This Article: ]

10.	Satokata I, Maas R. Msx1 deficient mice exhibit cleft palate and abnormalities of craniofacial and tooth development. Nat Genet. 1994;6:348-356. [PubMed] [DOI] [Cited in This Article: ]

11.	Zhao Y, Guo YJ, Tomac AC, Taylor NR, Grinberg A, Lee EJ, Huang S, Westphal H. Isolated cleft palate in mice with a targeted mutation of the LIM homeobox gene lhx8. Proc Natl Acad Sci USA. 1999;96:15002-15006. [PubMed] [DOI] [Cited in This Article: ]

12.	Ito Y, Yeo JY, Chytil A, Han J, Bringas P, Nakajima A, Shuler CF, Moses HL, Chai Y. Conditional inactivation of Tgfbr2 in cranial neural crest causes cleft palate and calvaria defects. Development. 2003;130:5269-5280. [PubMed] [DOI] [Cited in This Article: ]

13.	Rice R, Spencer-Dene B, Connor EC, Gritli-Linde A, McMahon AP, Dickson C, Thesleff I, Rice DP. Disruption of Fgf10/Fgfr2b-coordinated epithelial-mesenchymal interactions causes cleft palate. J Clin Invest. 2004;113:1692-1700. [PubMed] [DOI] [Cited in This Article: ]

14.	Jin JZ, Ding J. Analysis of cell migration, transdifferentiation and apoptosis during mouse secondary palate fusion. Development. 2006;133:3341-3347. [PubMed] [DOI] [Cited in This Article: ]

15.	Kaartinen V, Voncken JW, Shuler C, Warburton D, Bu D, Heisterkamp N, Groffen J. Abnormal lung development and cleft palate in mice lacking TGF-beta 3 indicates defects of epithelial-mesenchymal interaction. Nat Genet. 1995;11:415-421. [PubMed] [DOI] [Cited in This Article: ]

16.	Proetzel G, Pawlowski SA, Wiles MV, Yin M, Boivin GP, Howles PN, Ding J, Ferguson MW, Doetschman T. Transforming growth factor-beta 3 is required for secondary palate fusion. Nat Genet. 1995;11:409-414. [PubMed] [DOI] [Cited in This Article: ]

17.	Miettinen PJ, Chin JR, Shum L, Slavkin HC, Shuler CF, Derynck R, Werb Z. Epidermal growth factor receptor function is necessary for normal craniofacial development and palate closure. Nat Genet. 1999;22:69-73. [PubMed] [DOI] [Cited in This Article: ]

18.	Taya Y, O’Kane S, Ferguson MW. Pathogenesis of cleft palate in TGF-beta3 knockout mice. Development. 1999;126:3869-3879. [PubMed] [DOI] [Cited in This Article: ]

19.	Gendron-Maguire M, Mallo M, Zhang M, Gridley T. Hoxa-2 mutant mice exhibit homeotic transformation of skeletal elements derived from cranial neural crest. Cell. 1993;75:1317-1331. [PubMed] [DOI] [Cited in This Article: ]

20.	Barrow JR, Capecchi MR. Compensatory defects associated with mutations in Hoxa1 restore normal palatogenesis to Hoxa2 mutants. Development. 1999;126:5011-5026. [PubMed] [DOI] [Cited in This Article: ]

21.	Hilliard SA, Yu L, Gu S, Zhang Z, Chen YP. Regional regulation of palatal growth and patterning along the anterior-posterior axis in mice. J Anat. 2005;207:655-667. [PubMed] [DOI] [Cited in This Article: ]

22.	Yu L, Gu S, Alappat S, Song Y, Yan M, Zhang X, Zhang G, Jiang Y, Zhang Z, Zhang Y. Shox2-deficient mice exhibit a rare type of incomplete clefting of the secondary palate. Development. 2005;132:4397-4406. [PubMed] [DOI] [Cited in This Article: ]

23.	Zhang Z, Song Y, Zhao X, Zhang X, Fermin C, Chen Y. Rescue of cleft palate in Msx1-deficient mice by transgenic Bmp4 reveals a network of BMP and Shh signaling in the regulation of mammalian palatogenesis. Development. 2002;129:4135-4146. [PubMed] [DOI] [Cited in This Article: ]

24.	Parrish M, Ott T, Lance-Jones C, Schuetz G, Schwaeger-Nickolenko A, Monaghan AP. Loss of the Sall3 gene leads to palate deficiency, abnormalities in cranial nerves, and perinatal lethality. Mol Cell Biol. 2004;24:7102-7112. [PubMed] [DOI] [Cited in This Article: ]

25.	Yagi H, Furutani Y, Hamada H, Sasaki T, Asakawa S, Minoshima S, Ichida F, Joo K, Kimura M, Imamura S. Role of TBX1 in human del22q11.2 syndrome. Lancet. 2003;362:1366-1373. [PubMed] [DOI] [Cited in This Article: ]

26.

Barron MJ, Brookes SJ, Draper CE, Garrod D, Kirkham J, Shore RC, Dixon MJ. The cell adhesion molecule nectin-1 is critical for normal enamel formation in mice. Hum Mol Genet. 2008;17:3509-3520. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 52] [Cited by in F6Publishing: 51] [Article Influence: 3.2] [Reference Citation Analysis (0)]

27.	Jugessur A, Murray JC. Orofacial clefting: recent insights into a complex trait. Curr Opin Genet Dev. 2005;15:270-278. [PubMed] [DOI] [Cited in This Article: ]

28.

Mukhopadhyay P, Brock G, Pihur V, Webb C, Pisano MM, Greene RM. Developmental microRNA expression profiling of murine embryonic orofacial tissue. Birth Defects Res A Clin Mol Teratol. 2010;88:511-534. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 36] [Cited by in F6Publishing: 40] [Article Influence: 2.9] [Reference Citation Analysis (0)]

29.

Barritt LC, Miller JM, Scheetz LR, Gardner K, Pierce ML, Soukup GA, Rocha-Sanchez SM. Conditional deletion of the human ortholog gene Dicer1 in Pax2-Cre expression domain impairs orofacial development. Indian J Hum Genet. 2012;18:310-319. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 23] [Cited by in F6Publishing: 26] [Article Influence: 2.4] [Reference Citation Analysis (0)]

30.

Nakamura Y, Inloes JB, Katagiri T, Kobayashi T. Chondrocyte-specific microRNA-140 regulates endochondral bone development and targets Dnpep to modulate bone morphogenetic protein signaling. Mol Cell Biol. 2011;31:3019-3028. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 121] [Cited by in F6Publishing: 135] [Article Influence: 10.4] [Reference Citation Analysis (0)]

31.

Wang J, Bai Y, Li H, Greene SB, Klysik E, Yu W, Schwartz RJ, Williams TJ, Martin JF. MicroRNA-17-92, a direct Ap-2α transcriptional target, modulates T-box factor activity in orofacial clefting. PLoS Genet. 2013;9:e1003785. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 50] [Cited by in F6Publishing: 58] [Article Influence: 5.3] [Reference Citation Analysis (0)]

32.

Su X, Chakravarti D, Cho MS, Liu L, Gi YJ, Lin YL, Leung ML, El-Naggar A, Creighton CJ, Suraokar MB. TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs. Nature. 2010;467:986-990. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 351] [Cited by in F6Publishing: 356] [Article Influence: 25.4] [Reference Citation Analysis (0)]

33.	Dudas M, Sridurongrit S, Nagy A, Okazaki K, Kaartinen V. Craniofacial defects in mice lacking BMP type I receptor Alk2 in neural crest cells. Mech Dev. 2004;121:173-182. [PubMed] [DOI] [Cited in This Article: ]

34.	Matzuk MM, Kumar TR, Bradley A. Different phenotypes for mice deficient in either activins or activin receptor type II. Nature. 1995;374:356-360. [PubMed] [DOI] [Cited in This Article: ]

35.	Liu W, Sun X, Braut A, Mishina Y, Behringer RR, Mina M, Martin JF. Distinct functions for Bmp signaling in lip and palate fusion in mice. Development. 2005;132:1453-1461. [PubMed] [DOI] [Cited in This Article: ]

36.

Kouskoura T, Kozlova A, Alexiou M, Blumer S, Zouvelou V, Katsaros C, Chiquet M, Mitsiadis TA, Graf D. The etiology of cleft palate formation in BMP7-deficient mice. PLoS One. 2013;8:e59463. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 31] [Cited by in F6Publishing: 31] [Article Influence: 2.8] [Reference Citation Analysis (0)]

37.	Bachiller D, Klingensmith J, Shneyder N, Tran U, Anderson R, Rossant J, De Robertis EM. The role of chordin/Bmp signals in mammalian pharyngeal development and DiGeorge syndrome. Development. 2003;130:3567-3578. [PubMed] [DOI] [Cited in This Article: ]

38.	Ivkovic S, Yoon BS, Popoff SN, Safadi FF, Libuda DE, Stephenson RC, Daluiski A, Lyons KM. Connective tissue growth factor coordinates chondrogenesis and angiogenesis during skeletal development. Development. 2003;130:2779-2791. [PubMed] [DOI] [Cited in This Article: ]

39.	Kurihara Y, Kurihara H, Suzuki H, Kodama T, Maemura K, Nagai R, Oda H, Kuwaki T, Cao WH, Kamada N. Elevated blood pressure and craniofacial abnormalities in mice deficient in endothelin-1. Nature. 1994;368:703-710. [PubMed] [DOI] [Cited in This Article: ]

40.	Colvin JS, White AC, Pratt SJ, Ornitz DM. Lung hypoplasia and neonatal death in Fgf9-null mice identify this gene as an essential regulator of lung mesenchyme. Development. 2001;128:2095-2106. [PubMed] [DOI] [Cited in This Article: ]

41.	Alappat SR, Zhang Z, Suzuki K, Zhang X, Liu H, Jiang R, Yamada G, Chen Y. The cellular and molecular etiology of the cleft secondary palate in Fgf10 mutant mice. Dev Biol. 2005;277:102-113. [PubMed] [DOI] [Cited in This Article: ]

42.	Liu Z, Xu J, Colvin JS, Ornitz DM. Coordination of chondrogenesis and osteogenesis by fibroblast growth factor 18. Genes Dev. 2002;16:859-869. [PubMed] [DOI] [Cited in This Article: ]

43.	Ohbayashi N, Shibayama M, Kurotaki Y, Imanishi M, Fujimori T, Itoh N, Takada S. FGF18 is required for normal cell proliferation and differentiation during osteogenesis and chondrogenesis. Genes Dev. 2002;16:870-879. [PubMed] [DOI] [Cited in This Article: ]

44.	Trokovic N, Trokovic R, Mai P, Partanen J. Fgfr1 regulates patterning of the pharyngeal region. Genes Dev. 2003;17:141-153. [PubMed] [DOI] [Cited in This Article: ]

45.

De Moerlooze L, Spencer-Dene B, Revest JM, Hajihosseini M, Rosewell I, Dickson C. An important role for the IIIb isoform of fibroblast growth factor receptor 2 (FGFR2) in mesenchymal-epithelial signalling during mouse organogenesis. Development. 2000;127:483-492. [PubMed] [Cited in This Article: ]

46.	Matzuk MM, Lu N, Vogel H, Sellheyer K, Roop DR, Bradley A. Multiple defects and perinatal death in mice deficient in follistatin. Nature. 1995;374:360-363. [PubMed] [DOI] [Cited in This Article: ]

47.

Homanics GE, DeLorey TM, Firestone LL, Quinlan JJ, Handforth A, Harrison NL, Krasowski MD, Rick CE, Korpi ER, Mäkelä R. Mice devoid of gamma-aminobutyrate type A receptor beta3 subunit have epilepsy, cleft palate, and hypersensitive behavior. Proc Natl Acad Sci USA. 1997;94:4143-4148. [PubMed] [Cited in This Article: ]

48.	Lee YS, Lee SJ. Regulation of GDF-11 and myostatin activity by GASP-1 and GASP-2. Proc Natl Acad Sci USA. 2013;110:E3713-E3722. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 68] [Cited by in F6Publishing: 72] [Article Influence: 6.5] [Reference Citation Analysis (0)]

49.

Anderson KD, Pan L, Yang XM, Hughes VC, Walls JR, Dominguez MG, Simmons MV, Burfeind P, Xue Y, Wei Y. Angiogenic sprouting into neural tissue requires Gpr124, an orphan G protein-coupled receptor. Proc Natl Acad Sci USA. 2011;108:2807-2812. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 108] [Cited by in F6Publishing: 114] [Article Influence: 8.8] [Reference Citation Analysis (0)]

50.	Matzuk MM, Kumar TR, Vassalli A, Bickenbach JR, Roop DR, Jaenisch R, Bradley A. Functional analysis of activins during mammalian development. Nature. 1995;374:354-356. [PubMed] [DOI] [Cited in This Article: ]

51.	Ding H, Wu X, Boström H, Kim I, Wong N, Tsoi B, O’Rourke M, Koh GY, Soriano P, Betsholtz C. A specific requirement for PDGF-C in palate formation and PDGFR-alpha signaling. Nat Genet. 2004;36:1111-1116. [PubMed] [DOI] [Cited in This Article: ]

52.

Choi SJ, Marazita ML, Hart PS, Sulima PP, Field LL, McHenry TG, Govil M, Cooper ME, Letra A, Menezes R. The PDGF-C regulatory region SNP rs28999109 decreases promoter transcriptional activity and is associated with CL/P. Eur J Hum Genet. 2009;17:774-784. [PubMed] [Cited in This Article: ]

53.	Morrison-Graham K, Schatteman GC, Bork T, Bowen-Pope DF, Weston JA. A PDGF receptor mutation in the mouse (Patch) perturbs the development of a non-neuronal subset of neural crest-derived cells. Development. 1992;115:133-142. [PubMed] [DOI] [Cited in This Article: ]

54.	Tallquist MD, Soriano P. Cell autonomous requirement for PDGFRalpha in populations of cranial and cardiac neural crest cells. Development. 2003;130:507-518. [PubMed] [DOI] [Cited in This Article: ]

55.

Sanford LP, Ormsby I, Gittenberger-de Groot AC, Sariola H, Friedman R, Boivin GP, Cardell EL, Doetschman T. TGFbeta2 knockout mice have multiple developmental defects that are non-overlapping with other TGFbeta knockout phenotypes. Development. 1997;124:2659-2670. [PubMed] [Cited in This Article: ]

56.	Dudas M, Kim J, Li WY, Nagy A, Larsson J, Karlsson S, Chai Y, Kaartinen V. Epithelial and ectomesenchymal role of the type I TGF-beta receptor ALK5 during facial morphogenesis and palatal fusion. Dev Biol. 2006;296:298-314. [PubMed] [DOI] [Cited in This Article: ]

57.

Li WY, Dudas M, Kaartinen V. Signaling through Tgf-beta type I receptor Alk5 is required for upper lip fusion. Mech Dev. 2008;125:874-882. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 11] [Cited by in F6Publishing: 10] [Article Influence: 0.6] [Reference Citation Analysis (0)]

58.	Xu X, Han J, Ito Y, Bringas P, Urata MM, Chai Y. Cell autonomous requirement for Tgfbr2 in the disappearance of medial edge epithelium during palatal fusion. Dev Biol. 2006;297:238-248. [PubMed] [DOI] [Cited in This Article: ]

59.	Stalmans I, Lambrechts D, De Smet F, Jansen S, Wang J, Maity S, Kneer P, von der Ohe M, Swillen A, Maes C. VEGF: a modifier of the del22q11 (DiGeorge) syndrome? Nat Med. 2003;9:173-182. [PubMed] [DOI] [Cited in This Article: ]

60.

Mima J, Koshino A, Oka K, Uchida H, Hieda Y, Nohara K, Kogo M, Chai Y, Sakai T. Regulation of the epithelial adhesion molecule CEACAM1 is important for palate formation. PLoS One. 2013;8:e61653. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 11] [Cited by in F6Publishing: 13] [Article Influence: 1.2] [Reference Citation Analysis (0)]

61.	Holmberg J, Clarke DL, Frisén J. Regulation of repulsion versus adhesion by different splice forms of an Eph receptor. Nature. 2000;408:203-206. [PubMed] [DOI] [Cited in This Article: ]

62.	Compagni A, Logan M, Klein R, Adams RH. Control of skeletal patterning by ephrinB1-EphB interactions. Dev Cell. 2003;5:217-230. [PubMed] [DOI] [Cited in This Article: ]

63.	Dravis C, Henkemeyer M. Ephrin-B reverse signaling controls septation events at the embryonic midline through separate tyrosine phosphorylation-independent signaling avenues. Dev Biol. 2011;355:138-151. [PubMed] [DOI] [Cited in This Article: ]

64.	Yu H, Smallwood PM, Wang Y, Vidaltamayo R, Reed R, Nathans J. Frizzled 1 and frizzled 2 genes function in palate, ventricular septum and neural tube closure: general implications for tissue fusion processes. Development. 2010;137:3707-3717. [PubMed] [DOI] [Cited in This Article: ]

65.	Bader BL, Rayburn H, Crowley D, Hynes RO. Extensive vasculogenesis, angiogenesis, and organogenesis precede lethality in mice lacking all alpha v integrins. Cell. 1998;95:507-519. [PubMed] [DOI] [Cited in This Article: ]

66.

Liang D, Wang X, Mittal A, Dhiman S, Hou SY, Degenhardt K, Astrof S. Mesodermal expression of integrin α5β1 regulates neural crest development and cardiovascular morphogenesis. Dev Biol. 2014;395:232-244. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 26] [Cited by in F6Publishing: 28] [Article Influence: 2.8] [Reference Citation Analysis (0)]

67.	Aszodi A, Hunziker EB, Brakebusch C, Fässler R. Beta1 integrins regulate chondrocyte rotation, G1 progression, and cytokinesis. Genes Dev. 2003;17:2465-2479. [PubMed] [DOI] [Cited in This Article: ]

68.	Zhu J, Motejlek K, Wang D, Zang K, Schmidt A, Reichardt LF. beta8 integrins are required for vascular morphogenesis in mouse embryos. Development. 2002;129:2891-2903. [PubMed] [DOI] [Cited in This Article: ]

69.

Humphreys R, Zheng W, Prince LS, Qu X, Brown C, Loomes K, Huppert SS, Baldwin S, Goudy S. Cranial neural crest ablation of Jagged1 recapitulates the craniofacial phenotype of Alagille syndrome patients. Hum Mol Genet. 2012;21:1374-1383. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 58] [Cited by in F6Publishing: 59] [Article Influence: 4.5] [Reference Citation Analysis (0)]

70.	Jiang R, Lan Y, Chapman HD, Shawber C, Norton CR, Serreze DV, Weinmaster G, Gridley T. Defects in limb, craniofacial, and thymic development in Jagged2 mutant mice. Genes Dev. 1998;12:1046-1057. [PubMed] [DOI] [Cited in This Article: ]

71.	Zaritsky JJ, Eckman DM, Wellman GC, Nelson MT, Schwarz TL. Targeted disruption of Kir2.1 and Kir2.2 genes reveals the essential role of the inwardly rectifying K(+) current in K(+)-mediated vasodilation. Circ Res. 2000;87:160-166. [PubMed] [DOI] [Cited in This Article: ]

72.

Song L, Li Y, Wang K, Wang YZ, Molotkov A, Gao L, Zhao T, Yamagami T, Wang Y, Gan Q. Lrp6-mediated canonical Wnt signaling is required for lip formation and fusion. Development. 2009;136:3161-3171. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 117] [Cited by in F6Publishing: 120] [Article Influence: 8.0] [Reference Citation Analysis (0)]

73.	Schwabe GC, Trepczik B, Süring K, Brieske N, Tucker AS, Sharpe PT, Minami Y, Mundlos S. Ror2 knockout mouse as a model for the developmental pathology of autosomal recessive Robinow syndrome. Dev Dyn. 2004;229:400-410. [PubMed] [DOI] [Cited in This Article: ]

74.	Halford MM, Armes J, Buchert M, Meskenaite V, Grail D, Hibbs ML, Wilks AF, Farlie PG, Newgreen DF, Hovens CM. Ryk-deficient mice exhibit craniofacial defects associated with perturbed Eph receptor crosstalk. Nat Genet. 2000;25:414-418. [PubMed] [DOI] [Cited in This Article: ]

75.

Zvaritch E, Depreux F, Kraeva N, Loy RE, Goonasekera SA, Boncompagni S, Kraev A, Gramolini AO, Dirksen RT, Franzini-Armstrong C. An Ryr1I4895T mutation abolishes Ca2+ release channel function and delays development in homozygous offspring of a mutant mouse line. Proc Natl Acad Sci USA. 2007;104:18537-18542. [PubMed] [Cited in This Article: ]

76.

Krakowiak PA, Wassif CA, Kratz L, Cozma D, Kovárová M, Harris G, Grinberg A, Yang Y, Hunter AG, Tsokos M. Lathosterolosis: an inborn error of human and murine cholesterol synthesis due to lathosterol 5-desaturase deficiency. Hum Mol Genet. 2003;12:1631-1641. [PubMed] [Cited in This Article: ]

77.	Huang X, Litingtung Y, Chiang C. Ectopic sonic hedgehog signaling impairs telencephalic dorsal midline development: implication for human holoprosencephaly. Hum Mol Genet. 2007;16:1454-1468. [PubMed] [DOI] [Cited in This Article: ]

78.	Jeong J, Mao J, Tenzen T, Kottmann AH, McMahon AP. Hedgehog signaling in the neural crest cells regulates the patterning and growth of facial primordia. Genes Dev. 2004;18:937-951. [PubMed] [DOI] [Cited in This Article: ]

79.

Sang L, Miller JJ, Corbit KC, Giles RH, Brauer MJ, Otto EA, Baye LM, Wen X, Scales SJ, Kwong M. Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes and pathways. Cell. 2011;145:513-528. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 455] [Cited by in F6Publishing: 460] [Article Influence: 35.4] [Reference Citation Analysis (0)]

80.

Fu J, Ivy Yu HM, Maruyama T, Mirando AJ, Hsu W. Gpr177/mouse Wntless is essential for Wnt-mediated craniofacial and brain development. Dev Dyn. 2011;240:365-371. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 78] [Cited by in F6Publishing: 81] [Article Influence: 6.2] [Reference Citation Analysis (0)]

81.	Yamaguchi TP, Bradley A, McMahon AP, Jones S. A Wnt5a pathway underlies outgrowth of multiple structures in the vertebrate embryo. Development. 1999;126:1211-1223. [PubMed] [DOI] [Cited in This Article: ]

82.	Carroll TJ, Park JS, Hayashi S, Majumdar A, McMahon AP. Wnt9b plays a central role in the regulation of mesenchymal to epithelial transitions underlying organogenesis of the mammalian urogenital system. Dev Cell. 2005;9:283-292. [PubMed] [DOI] [Cited in This Article: ]

83.

Ferretti E, Li B, Zewdu R, Wells V, Hebert JM, Karner C, Anderson MJ, Williams T, Dixon J, Dixon MJ. A conserved Pbx-Wnt-p63-Irf6 regulatory module controls face morphogenesis by promoting epithelial apoptosis. Dev Cell. 2011;21:627-641. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 132] [Cited by in F6Publishing: 146] [Article Influence: 11.2] [Reference Citation Analysis (0)]

84.

Uz E, Alanay Y, Aktas D, Vargel I, Gucer S, Tuncbilek G, von Eggeling F, Yilmaz E, Deren O, Posorski N. Disruption of ALX1 causes extreme microphthalmia and severe facial clefting: expanding the spectrum of autosomal-recessive ALX-related frontonasal dysplasia. Am J Hum Genet. 2010;86:789-796. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 108] [Cited by in F6Publishing: 102] [Article Influence: 7.3] [Reference Citation Analysis (0)]

85.	Beverdam A, Brouwer A, Reijnen M, Korving J, Meijlink F. Severe nasal clefting and abnormal embryonic apoptosis in Alx3/Alx4 double mutant mice. Development. 2001;128:3975-3986. [PubMed] [DOI] [Cited in This Article: ]

86.

Reilly PT, Afzal S, Gorrini C, Lui K, Bukhman YV, Wakeham A, Haight J, Ling TW, Cheung CC, Elia AJ. Acidic nuclear phosphoprotein 32kDa (ANP32)B-deficient mouse reveals a hierarchy of ANP32 importance in mammalian development. Proc Natl Acad Sci USA. 2011;108:10243-10248. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 30] [Cited by in F6Publishing: 34] [Article Influence: 2.6] [Reference Citation Analysis (0)]

87.	Schmahl J, Raymond CS, Soriano P. PDGF signaling specificity is mediated through multiple immediate early genes. Nat Genet. 2007;39:52-60. [PubMed] [DOI] [Cited in This Article: ]

88.

Abdel-Wahab O, Gao J, Adli M, Dey A, Trimarchi T, Chung YR, Kuscu C, Hricik T, Ndiaye-Lobry D, Lafave LM. Deletion of Asxl1 results in myelodysplasia and severe developmental defects in vivo. J Exp Med. 2013;210:2641-2659. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 227] [Cited by in F6Publishing: 267] [Article Influence: 24.3] [Reference Citation Analysis (0)]

89.

Miletich I, Yu WY, Zhang R, Yang K, Caixeta de Andrade S, Pereira SF, Ohazama A, Mock OB, Buchner G, Sealby J. Developmental stalling and organ-autonomous regulation of morphogenesis. Proc Natl Acad Sci USA. 2011;108:19270-19275. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 32] [Cited by in F6Publishing: 33] [Article Influence: 2.5] [Reference Citation Analysis (0)]

90.

Aizawa R, Yamada A, Suzuki D, Iimura T, Kassai H, Harada T, Tsukasaki M, Yamamoto G, Tachikawa T, Nakao K. Cdc42 is required for chondrogenesis and interdigital programmed cell death during limb development. Mech Dev. 2012;129:38-50. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 35] [Cited by in F6Publishing: 30] [Article Influence: 2.5] [Reference Citation Analysis (0)]

91.	Bosman EA, Penn AC, Ambrose JC, Kettleborough R, Stemple DL, Steel KP. Multiple mutations in mouse Chd7 provide models for CHARGE syndrome. Hum Mol Genet. 2005;14:3463-3476. [PubMed] [DOI] [Cited in This Article: ]

92.

Sperry ED, Hurd EA, Durham MA, Reamer EN, Stein AB, Martin DM. The chromatin remodeling protein CHD7, mutated in CHARGE syndrome, is necessary for proper craniofacial and tracheal development. Dev Dyn. 2014;243:1055-1066. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 29] [Cited by in F6Publishing: 29] [Article Influence: 2.9] [Reference Citation Analysis (0)]

93.

Bentham J, Michell AC, Lockstone H, Andrew D, Schneider JE, Brown NA, Bhattacharya S. Maternal high-fat diet interacts with embryonic Cited2 genotype to reduce Pitx2c expression and enhance penetrance of left-right patterning defects. Hum Mol Genet. 2010;19:3394-3401. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 29] [Cited by in F6Publishing: 28] [Article Influence: 2.0] [Reference Citation Analysis (0)]

94.	Kasper LH, Boussouar F, Boyd K, Xu W, Biesen M, Rehg J, Baudino TA, Cleveland JL, Brindle PK. Two transactivation mechanisms cooperate for the bulk of HIF-1-responsive gene expression. EMBO J. 2005;24:3846-3858. [PubMed] [DOI] [Cited in This Article: ]

95.

Qiu M, Bulfone A, Ghattas I, Meneses JJ, Christensen L, Sharpe PT, Presley R, Pedersen RA, Rubenstein JL. Role of the Dlx homeobox genes in proximodistal patterning of the branchial arches: mutations of Dlx-1, Dlx-2, and Dlx-1 and -2 alter morphogenesis of proximal skeletal and soft tissue structures derived from the first and second arches. Dev Biol. 1997;185:165-184. [PubMed] [Cited in This Article: ]

96.	Acampora D, Merlo GR, Paleari L, Zerega B, Postiglione MP, Mantero S, Bober E, Barbieri O, Simeone A, Levi G. Craniofacial, vestibular and bone defects in mice lacking the Distal-less-related gene Dlx5. Development. 1999;126:3795-3809. [PubMed] [DOI] [Cited in This Article: ]

97.	Depew MJ, Liu JK, Long JE, Presley R, Meneses JJ, Pedersen RA, Rubenstein JL. Dlx5 regulates regional development of the branchial arches and sensory capsules. Development. 1999;126:3831-3846. [PubMed] [DOI] [Cited in This Article: ]

98.	Chen CM, Behringer RR. Ovca1 regulates cell proliferation, embryonic development, and tumorigenesis. Genes Dev. 2004;18:320-332. [PubMed] [DOI] [Cited in This Article: ]

99.	Xu PX, Adams J, Peters H, Brown MC, Heaney S, Maas R. Eya1-deficient mice lack ears and kidneys and show abnormal apoptosis of organ primordia. Nat Genet. 1999;23:113-117. [PubMed] [DOI] [Cited in This Article: ]

100.

Iida K, Koseki H, Kakinuma H, Kato N, Mizutani-Koseki Y, Ohuchi H, Yoshioka H, Noji S, Kawamura K, Kataoka Y. Essential roles of the winged helix transcription factor MFH-1 in aortic arch patterning and skeletogenesis. Development. 1997;124:4627-4638. [PubMed] [Cited in This Article: ]

101.

Teng L, Mundell NA, Frist AY, Wang Q, Labosky PA. Requirement for Foxd3 in the maintenance of neural crest progenitors. Development. 2008;135:1615-1624. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 140] [Cited by in F6Publishing: 142] [Article Influence: 8.9] [Reference Citation Analysis (0)]

102.	De Felice M, Ovitt C, Biffali E, Rodriguez-Mallon A, Arra C, Anastassiadis K, Macchia PE, Mattei MG, Mariano A, Schöler H. A mouse model for hereditary thyroid dysgenesis and cleft palate. Nat Genet. 1998;19:395-398. [PubMed] [DOI] [Cited in This Article: ]

103.	Wang T, Tamakoshi T, Uezato T, Shu F, Kanzaki-Kato N, Fu Y, Koseki H, Yoshida N, Sugiyama T, Miura N. Forkhead transcription factor Foxf2 (LUN)-deficient mice exhibit abnormal development of secondary palate. Dev Biol. 2003;259:83-94. [PubMed] [DOI] [Cited in This Article: ]

104.	Byrd NA, Meyers EN. Loss of Gbx2 results in neural crest cell patterning and pharyngeal arch artery defects in the mouse embryo. Dev Biol. 2005;284:233-245. [PubMed] [DOI] [Cited in This Article: ]

105.

Huang X, Goudy SL, Ketova T, Litingtung Y, Chiang C. Gli3-deficient mice exhibit cleft palate associated with abnormal tongue development. Dev Dyn. 2008;237:3079-3087. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 35] [Cited by in F6Publishing: 37] [Article Influence: 2.3] [Reference Citation Analysis (0)]

106.	Yamada G, Mansouri A, Torres M, Stuart ET, Blum M, Schultz M, De Robertis EM, Gruss P. Targeted mutation of the murine goosecoid gene results in craniofacial defects and neonatal death. Development. 1995;121:2917-2922. [PubMed] [DOI] [Cited in This Article: ]

107.	Yanagisawa H, Clouthier DE, Richardson JA, Charité J, Olson EN. Targeted deletion of a branchial arch-specific enhancer reveals a role of dHAND in craniofacial development. Development. 2003;130:1069-1078. [PubMed] [DOI] [Cited in This Article: ]

108.

Carter MG, Johns MA, Zeng X, Zhou L, Zink MC, Mankowski JL, Donovan DM, Baylin SB. Mice deficient in the candidate tumor suppressor gene Hic1 exhibit developmental defects of structures affected in the Miller-Dieker syndrome. Hum Mol Genet. 2000;9:413-419. [PubMed] [Cited in This Article: ]

109.	Ingraham CR, Kinoshita A, Kondo S, Yang B, Sajan S, Trout KJ, Malik MI, Dunnwald M, Goudy SL, Lovett M. Abnormal skin, limb and craniofacial morphogenesis in mice deficient for interferon regulatory factor 6 (Irf6). Nat Genet. 2006;38:1335-1340. [PubMed] [DOI] [Cited in This Article: ]

110.	Richardson RJ, Dixon J, Malhotra S, Hardman MJ, Knowles L, Boot-Handford RP, Shore P, Whitmarsh A, Dixon MJ. Irf6 is a key determinant of the keratinocyte proliferation-differentiation switch. Nat Genet. 2006;38:1329-1334. [PubMed] [DOI] [Cited in This Article: ]

111.	Böse J, Gruber AD, Helming L, Schiebe S, Wegener I, Hafner M, Beales M, Köntgen F, Lengeling A. The phosphatidylserine receptor has essential functions during embryogenesis but not in apoptotic cell removal. J Biol. 2004;3:15. [PubMed] [DOI] [Cited in This Article: ]

112.	Thomas T, Corcoran LM, Gugasyan R, Dixon MP, Brodnicki T, Nutt SL, Metcalf D, Voss AK. Monocytic leukemia zinc finger protein is essential for the development of long-term reconstituting hematopoietic stem cells. Genes Dev. 2006;20:1175-1186. [PubMed] [DOI] [Cited in This Article: ]

113.

Denaxa M, Sharpe PT, Pachnis V. The LIM homeodomain transcription factors Lhx6 and Lhx7 are key regulators of mammalian dentition. Dev Biol. 2009;333:324-336. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 55] [Cited by in F6Publishing: 58] [Article Influence: 3.9] [Reference Citation Analysis (0)]

114.

Hsu CY, Chang NC, Lee MW, Lee KH, Sun DS, Lai C, Chang AC. LUZP deficiency affects neural tube closure during brain development. Biochem Biophys Res Commun. 2008;376:466-471. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 28] [Cited by in F6Publishing: 30] [Article Influence: 1.9] [Reference Citation Analysis (0)]

115.	Verzi MP, Agarwal P, Brown C, McCulley DJ, Schwarz JJ, Black BL. The transcription factor MEF2C is required for craniofacial development. Dev Cell. 2007;12:645-652. [PubMed] [DOI] [Cited in This Article: ]

116.	Jin JZ, Ding J. Analysis of Meox-2 mutant mice reveals a novel postfusion-based cleft palate. Dev Dyn. 2006;235:539-546. [PubMed] [DOI] [Cited in This Article: ]

117.

Meester-Smoor MA, Vermeij M, van Helmond MJ, Molijn AC, van Wely KH, Hekman AC, Vermey-Keers C, Riegman PH, Zwarthoff EC. Targeted disruption of the Mn1 oncogene results in severe defects in development of membranous bones of the cranial skeleton. Mol Cell Biol. 2005;25:4229-4236. [PubMed] [Cited in This Article: ]

118.

Toyo-oka K, Hirotsune S, Gambello MJ, Zhou ZQ, Olson L, Rosenfeld MG, Eisenman R, Hurlin P, Wynshaw-Boris A. Loss of the Max-interacting protein Mnt in mice results in decreased viability, defective embryonic growth and craniofacial defects: relevance to Miller-Dieker syndrome. Hum Mol Genet. 2004;13:1057-1067. [PubMed] [Cited in This Article: ]

119.	Winograd J, Reilly MP, Roe R, Lutz J, Laughner E, Xu X, Hu L, Asakura T, vander Kolk C, Strandberg JD. Perinatal lethality and multiple craniofacial malformations in MSX2 transgenic mice. Hum Mol Genet. 1997;6:369-379. [PubMed] [DOI] [Cited in This Article: ]

120.

Shi W, Bain AL, Schwer B, Al-Ejeh F, Smith C, Wong L, Chai H, Miranda MS, Ho U, Kawaguchi M. Essential developmental, genomic stability, and tumour suppressor functions of the mouse orthologue of hSSB1/NABP2. PLoS Genet. 2013;9:e1003298. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 23] [Cited by in F6Publishing: 25] [Article Influence: 2.3] [Reference Citation Analysis (0)]

121.

Feldhahn N, Ferretti E, Robbiani DF, Callen E, Deroubaix S, Selleri L, Nussenzweig A, Nussenzweig MC. The hSSB1 orthologue Obfc2b is essential for skeletogenesis but dispensable for the DNA damage response in vivo. EMBO J. 2012;31:4045-4056. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 21] [Cited by in F6Publishing: 23] [Article Influence: 1.9] [Reference Citation Analysis (0)]

122.

Ross AP, Mansilla MA, Choe Y, Helminski S, Sturm R, Maute RL, May SR, Hozyasz KK, Wójcicki P, Mostowska A. A mutation in mouse Pak1ip1 causes orofacial clefting while human PAK1IP1 maps to 6p24 translocation breaking points associated with orofacial clefting. PLoS One. 2013;8:e69333. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 7] [Cited by in F6Publishing: 7] [Article Influence: 0.6] [Reference Citation Analysis (0)]

123.	Zhang B, Jain S, Song H, Fu M, Heuckeroth RO, Erlich JM, Jay PY, Milbrandt J. Mice lacking sister chromatid cohesion protein PDS5B exhibit developmental abnormalities reminiscent of Cornelia de Lange syndrome. Development. 2007;134:3191-3201. [PubMed] [DOI] [Cited in This Article: ]

124.

Takihara Y, Tomotsune D, Shirai M, Katoh-Fukui Y, Nishii K, Motaleb MA, Nomura M, Tsuchiya R, Fujita Y, Shibata Y. Targeted disruption of the mouse homologue of the Drosophila polyhomeotic gene leads to altered anteroposterior patterning and neural crest defects. Development. 1997;124:3673-3682. [PubMed] [Cited in This Article: ]

125.	Lanctôt C, Moreau A, Chamberland M, Tremblay ML, Drouin J. Hindlimb patterning and mandible development require the Ptx1 gene. Development. 1999;126:1805-1810. [PubMed] [DOI] [Cited in This Article: ]

126.	Lu MF, Pressman C, Dyer R, Johnson RL, Martin JF. Function of Rieger syndrome gene in left-right asymmetry and craniofacial development. Nature. 1999;401:276-278. [PubMed] [DOI] [Cited in This Article: ]

127.

Joo JH, Lee YJ, Munguba GC, Park S, Taxter TJ, Elsagga MY, Jackson MR, Oh SP, Sugrue SP. Role of Pinin in neural crest, dorsal dermis, and axial skeleton development and its involvement in the regulation of Tcf/Lef activity in mice. Dev Dyn. 2007;236:2147-2158. [PubMed] [Cited in This Article: ]

128.

Bjork BC, Turbe-Doan A, Prysak M, Herron BJ, Beier DR. Prdm16 is required for normal palatogenesis in mice. Hum Mol Genet. 2010;19:774-789. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 96] [Cited by in F6Publishing: 108] [Article Influence: 7.2] [Reference Citation Analysis (0)]

129.	Martin JF, Bradley A, Olson EN. The paired-like homeo box gene MHox is required for early events of skeletogenesis in multiple lineages. Genes Dev. 1995;9:1237-1249. [PubMed] [DOI] [Cited in This Article: ]

130.

Metzis V, Courtney AD, Kerr MC, Ferguson C, Rondón Galeano MC, Parton RG, Wainwright BJ, Wicking C. Patched1 is required in neural crest cells for the prevention of orofacial clefts. Hum Mol Genet. 2013;22:5026-5035. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 31] [Cited by in F6Publishing: 32] [Article Influence: 2.9] [Reference Citation Analysis (0)]

131.	Schwab KR, Patterson LT, Hartman HA, Song N, Lang RA, Lin X, Potter SS. Pygo1 and Pygo2 roles in Wnt signaling in mammalian kidney development. BMC Biol. 2007;5:15. [PubMed] [DOI] [Cited in This Article: ]

132.	Voronina VA, Kozlov S, Mathers PH, Lewandoski M. Conditional alleles for activation and inactivation of the mouse Rx homeobox gene. Genesis. 2005;41:160-164. [PubMed] [DOI] [Cited in This Article: ]

133.	Mann MB, Hodges CA, Barnes E, Vogel H, Hassold TJ, Luo G. Defective sister-chromatid cohesion, aneuploidy and cancer predisposition in a mouse model of type II Rothmund-Thomson syndrome. Hum Mol Genet. 2005;14:813-825. [PubMed] [DOI] [Cited in This Article: ]

134.	Aberg T, Cavender A, Gaikwad JS, Bronckers AL, Wang X, Waltimo-Sirén J, Thesleff I, D’Souza RN. Phenotypic changes in dentition of Runx2 homozygote-null mutant mice. J Histochem Cytochem. 2004;52:131-139. [PubMed] [DOI] [Cited in This Article: ]

135.	Dobreva G, Chahrour M, Dautzenberg M, Chirivella L, Kanzler B, Fariñas I, Karsenty G, Grosschedl R. SATB2 is a multifunctional determinant of craniofacial patterning and osteoblast differentiation. Cell. 2006;125:971-986. [PubMed] [DOI] [Cited in This Article: ]

136.	Britanova O, Depew MJ, Schwark M, Thomas BL, Miletich I, Sharpe P, Tarabykin V. Satb2 haploinsufficiency phenocopies 2q32-q33 deletions, whereas loss suggests a fundamental role in the coordination of jaw development. Am J Hum Genet. 2006;79:668-678. [PubMed] [DOI] [Cited in This Article: ]

137.	Shamblott MJ, Bugg EM, Lawler AM, Gearhart JD. Craniofacial abnormalities resulting from targeted disruption of the murine Sim2 gene. Dev Dyn. 2002;224:373-380. [PubMed] [DOI] [Cited in This Article: ]

138.

Parada C, Li J, Iwata J, Suzuki A, Chai Y. CTGF mediates Smad-dependent transforming growth factor β signaling to regulate mesenchymal cell proliferation during palate development. Mol Cell Biol. 2013;33:3482-3493. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 45] [Cited by in F6Publishing: 53] [Article Influence: 4.8] [Reference Citation Analysis (0)]

139.

Papangeli I, Scambler PJ. Tbx1 genetically interacts with the transforming growth factor-β/bone morphogenetic protein inhibitor Smad7 during great vessel remodeling. Circ Res. 2013;112:90-102. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 41] [Cited by in F6Publishing: 34] [Article Influence: 2.8] [Reference Citation Analysis (0)]

140.	Murray SA, Oram KF, Gridley T. Multiple functions of Snail family genes during palate development in mice. Development. 2007;134:1789-1797. [PubMed] [DOI] [Cited in This Article: ]

141.	Smits P, Li P, Mandel J, Zhang Z, Deng JM, Behringer RR, de Crombrugghe B, Lefebvre V. The transcription factors L-Sox5 and Sox6 are essential for cartilage formation. Dev Cell. 2001;1:277-290. [PubMed] [DOI] [Cited in This Article: ]

142.	Bi W, Huang W, Whitworth DJ, Deng JM, Zhang Z, Behringer RR, de Crombrugghe B. Haploinsufficiency of Sox9 results in defective cartilage primordia and premature skeletal mineralization. Proc Natl Acad Sci USA. 2001;98:6698-6703. [PubMed] [DOI] [Cited in This Article: ]

143.	Mori-Akiyama Y, Akiyama H, Rowitch DH, de Crombrugghe B. Sox9 is required for determination of the chondrogenic cell lineage in the cranial neural crest. Proc Natl Acad Sci USA. 2003;100:9360-9365. [PubMed] [DOI] [Cited in This Article: ]

144.	Sock E, Rettig SD, Enderich J, Bösl MR, Tamm ER, Wegner M. Gene targeting reveals a widespread role for the high-mobility-group transcription factor Sox11 in tissue remodeling. Mol Cell Biol. 2004;24:6635-6644. [PubMed] [DOI] [Cited in This Article: ]

145.

Kasberg AD, Brunskill EW, Steven Potter S. SP8 regulates signaling centers during craniofacial development. Dev Biol. 2013;381:312-323. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 35] [Cited by in F6Publishing: 24] [Article Influence: 2.2] [Reference Citation Analysis (0)]

146.	Coré N, Caubit X, Metchat A, Boned A, Djabali M, Fasano L. Tshz1 is required for axial skeleton, soft palate and middle ear development in mice. Dev Biol. 2007;308:407-420. [PubMed] [DOI] [Cited in This Article: ]

147.	Jerome LA, Papaioannou VE. DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx1. Nat Genet. 2001;27:286-291. [PubMed] [DOI] [Cited in This Article: ]

148.

Zirzow S, Lüdtke TH, Brons JF, Petry M, Christoffels VM, Kispert A. Expression and requirement of T-box transcription factors Tbx2 and Tbx3 during secondary palate development in the mouse. Dev Biol. 2009;336:145-155. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 36] [Cited by in F6Publishing: 36] [Article Influence: 2.4] [Reference Citation Analysis (0)]

149.

Pauws E, Hoshino A, Bentley L, Prajapati S, Keller C, Hammond P, Martinez-Barbera JP, Moore GE, Stanier P. Tbx22null mice have a submucous cleft palate due to reduced palatal bone formation and also display ankyloglossia and choanal atresia phenotypes. Hum Mol Genet. 2009;18:4171-4179. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 71] [Cited by in F6Publishing: 73] [Article Influence: 4.9] [Reference Citation Analysis (0)]

150.	Dixon J, Brakebusch C, Fässler R, Dixon MJ. Increased levels of apoptosis in the prefusion neural folds underlie the craniofacial disorder, Treacher Collins syndrome. Hum Mol Genet. 2000;9:1473-1480. [PubMed] [DOI] [Cited in This Article: ]

151.	Brewer S, Feng W, Huang J, Sullivan S, Williams T. Wnt1-Cre-mediated deletion of AP-2alpha causes multiple neural crest-related defects. Dev Biol. 2004;267:135-152. [PubMed] [DOI] [Cited in This Article: ]

152.	Yang A, Schweitzer R, Sun D, Kaghad M, Walker N, Bronson RT, Tabin C, Sharpe A, Caput D, Crum C. p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature. 1999;398:714-718. [PubMed] [DOI] [Cited in This Article: ]

153.	Bertuzzi S, Hindges R, Mui SH, O’Leary DD, Lemke G. The homeodomain protein vax1 is required for axon guidance and major tract formation in the developing forebrain. Genes Dev. 1999;13:3092-3105. [PubMed] [DOI] [Cited in This Article: ]

154.

Nimura K, Ura K, Shiratori H, Ikawa M, Okabe M, Schwartz RJ, Kaneda Y. A histone H3 lysine 36 trimethyltransferase links Nkx2-5 to Wolf-Hirschhorn syndrome. Nature. 2009;460:287-291. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 281] [Cited by in F6Publishing: 295] [Article Influence: 19.7] [Reference Citation Analysis (0)]

155.

Kurima K, Hertzano R, Gavrilova O, Monahan K, Shpargel KB, Nadaraja G, Kawashima Y, Lee KY, Ito T, Higashi Y. A noncoding point mutation of Zeb1 causes multiple developmental malformations and obesity in Twirler mice. PLoS Genet. 2011;7:e1002307. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 23] [Cited by in F6Publishing: 25] [Article Influence: 1.9] [Reference Citation Analysis (0)]

156.

Jiang Z, Zhu L, Hu L, Slesnick TC, Pautler RG, Justice MJ, Belmont JW. Zic3 is required in the extra-cardiac perinodal region of the lateral plate mesoderm for left-right patterning and heart development. Hum Mol Genet. 2013;22:879-889. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 23] [Cited by in F6Publishing: 23] [Article Influence: 1.9] [Reference Citation Analysis (0)]

157.	Yang Y, Mahaffey CL, Bérubé N, Frankel WN. Interaction between fidgetin and protein kinase A-anchoring protein AKAP95 is critical for palatogenesis in the mouse. J Biol Chem. 2006;281:22352-22359. [PubMed] [DOI] [Cited in This Article: ]

158.	Cecconi F, Alvarez-Bolado G, Meyer BI, Roth KA, Gruss P. Apaf1 (CED-4 homolog) regulates programmed cell death in mammalian development. Cell. 1998;94:727-737. [PubMed] [DOI] [Cited in This Article: ]

159.

Dowdle WE, Robinson JF, Kneist A, Sirerol-Piquer MS, Frints SG, Corbit KC, Zaghloul NA, van Lijnschoten G, Mulders L, Verver DE. Disruption of a ciliary B9 protein complex causes Meckel syndrome. Am J Hum Genet. 2011;89:94-110. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 120] [Cited by in F6Publishing: 123] [Article Influence: 9.5] [Reference Citation Analysis (0)]

160.	Atasoy D, Schoch S, Ho A, Nadasy KA, Liu X, Zhang W, Mukherjee K, Nosyreva ED, Fernandez-Chacon R, Missler M. Deletion of CASK in mice is lethal and impairs synaptic function. Proc Natl Acad Sci USA. 2007;104:2525-2530. [PubMed] [DOI] [Cited in This Article: ]

161.	Yan Y, Frisén J, Lee MH, Massagué J, Barbacid M. Ablation of the CDK inhibitor p57Kip2 results in increased apoptosis and delayed differentiation during mouse development. Genes Dev. 1997;11:973-983. [PubMed] [DOI] [Cited in This Article: ]

162.

Zhang P, Liégeois NJ, Wong C, Finegold M, Hou H, Thompson JC, Silverman A, Harper JW, DePinho RA, Elledge SJ. Altered cell differentiation and proliferation in mice lacking p57KIP2 indicates a role in Beckwith-Wiedemann syndrome. Nature. 1997;387:151-158. [PubMed] [Cited in This Article: ]

163.	Li Q, Lu Q, Hwang JY, Büscher D, Lee KF, Izpisua-Belmonte JC, Verma IM. IKK1-deficient mice exhibit abnormal development of skin and skeleton. Genes Dev. 1999;13:1322-1328. [PubMed] [DOI] [Cited in This Article: ]

164.	Park TJ, Boyd K, Curran T. Cardiovascular and craniofacial defects in Crk-null mice. Mol Cell Biol. 2006;26:6272-6282. [PubMed] [DOI] [Cited in This Article: ]

165.

Lin C, Fisher AV, Yin Y, Maruyama T, Veith GM, Dhandha M, Huang GJ, Hsu W, Ma L. The inductive role of Wnt-β-Catenin signaling in the formation of oral apparatus. Dev Biol. 2011;356:40-50. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 60] [Cited by in F6Publishing: 53] [Article Influence: 4.1] [Reference Citation Analysis (0)]

166.

He F, Xiong W, Wang Y, Li L, Liu C, Yamagami T, Taketo MM, Zhou C, Chen Y. Epithelial Wnt/β-catenin signaling regulates palatal shelf fusion through regulation of Tgfβ3 expression. Dev Biol. 2011;350:511-519. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 63] [Cited by in F6Publishing: 70] [Article Influence: 5.0] [Reference Citation Analysis (0)]

167.

Okano J, Kimura W, Papaionnou VE, Miura N, Yamada G, Shiota K, Sakai Y. The regulation of endogenous retinoic acid level through CYP26B1 is required for elevation of palatal shelves. Dev Dyn. 2012;241:1744-1756. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 26] [Cited by in F6Publishing: 26] [Article Influence: 2.2] [Reference Citation Analysis (0)]

168.

Keber R, Motaln H, Wagner KD, Debeljak N, Rassoulzadegan M, Ačimovič J, Rozman D, Horvat S. Mouse knockout of the cholesterogenic cytochrome P450 lanosterol 14alpha-demethylase (Cyp51) resembles Antley-Bixler syndrome. J Biol Chem. 2011;286:29086-29097. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 70] [Cited by in F6Publishing: 72] [Article Influence: 5.5] [Reference Citation Analysis (0)]

169.

Wassif CA, Zhu P, Kratz L, Krakowiak PA, Battaile KP, Weight FF, Grinberg A, Steiner RD, Nwokoro NA, Kelley RI. Biochemical, phenotypic and neurophysiological characterization of a genetic mouse model of RSH/Smith--Lemli--Opitz syndrome. Hum Mol Genet. 2001;10:555-564. [PubMed] [Cited in This Article: ]

170.

Fitzky BU, Moebius FF, Asaoka H, Waage-Baudet H, Xu L, Xu G, Maeda N, Kluckman K, Hiller S, Yu H. 7-Dehydrocholesterol-dependent proteolysis of HMG-CoA reductase suppresses sterol biosynthesis in a mouse model of Smith-Lemli-Opitz/RSH syndrome. J Clin Invest. 2001;108:905-915. [PubMed] [Cited in This Article: ]

171.

Adams MK, Belyaeva OV, Wu L, Kedishvili NY. The retinaldehyde reductase activity of DHRS3 is reciprocally activated by retinol dehydrogenase 10 to control retinoid homeostasis. J Biol Chem. 2014;289:14868-14880. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 77] [Cited by in F6Publishing: 68] [Article Influence: 6.8] [Reference Citation Analysis (0)]

172.

Billings SE, Pierzchalski K, Butler Tjaden NE, Pang XY, Trainor PA, Kane MA, Moise AR. The retinaldehyde reductase DHRS3 is essential for preventing the formation of excess retinoic acid during embryonic development. FASEB J. 2013;27:4877-4889. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 77] [Cited by in F6Publishing: 89] [Article Influence: 8.1] [Reference Citation Analysis (0)]

173.	Caruana G, Bernstein A. Craniofacial dysmorphogenesis including cleft palate in mice with an insertional mutation in the discs large gene. Mol Cell Biol. 2001;21:1475-1483. [PubMed] [DOI] [Cited in This Article: ]

174.

Zhang Z, Wlodarczyk BJ, Niederreither K, Venugopalan S, Florez S, Finnell RH, Amendt BA. Fuz regulates craniofacial development through tissue specific responses to signaling factors. PLoS One. 2011;6:e24608. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 41] [Cited by in F6Publishing: 44] [Article Influence: 3.4] [Reference Citation Analysis (0)]

175.	Schaeper U, Vogel R, Chmielowiec J, Huelsken J, Rosario M, Birchmeier W. Distinct requirements for Gab1 in Met and EGF receptor signaling in vivo. Proc Natl Acad Sci USA. 2007;104:15376-15381. [PubMed] [DOI] [Cited in This Article: ]

176.

Asada H, Kawamura Y, Maruyama K, Kume H, Ding RG, Kanbara N, Kuzume H, Sanbo M, Yagi T, Obata K. Cleft palate and decreased brain gamma-aminobutyric acid in mice lacking the 67-kDa isoform of glutamic acid decarboxylase. Proc Natl Acad Sci USA. 1997;94:6496-6499. [PubMed] [Cited in This Article: ]

177.	Condie BG, Bain G, Gottlieb DI, Capecchi MR. Cleft palate in mice with a targeted mutation in the gamma-aminobutyric acid-producing enzyme glutamic acid decarboxylase 67. Proc Natl Acad Sci USA. 1997;94:11451-11455. [PubMed] [DOI] [Cited in This Article: ]

178.

Li JP, Gong F, Hagner-McWhirter A, Forsberg E, Abrink M, Kisilevsky R, Zhang X, Lindahl U. Targeted disruption of a murine glucuronyl C5-epimerase gene results in heparan sulfate lacking L-iduronic acid and in neonatal lethality. J Biol Chem. 2003;278:28363-28366. [PubMed] [Cited in This Article: ]

179.

Miyaoka Y, Tanaka M, Imamura T, Takada S, Miyajima A. A novel regulatory mechanism for Fgf18 signaling involving cysteine-rich FGF receptor (Cfr) and delta-like protein (Dlk). Development. 2010;137:159-167. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 21] [Cited by in F6Publishing: 21] [Article Influence: 1.5] [Reference Citation Analysis (0)]

180.	Saxton TM, Cheng AM, Ong SH, Lu Y, Sakai R, Cross JC, Pawson T. Gene dosage-dependent functions for phosphotyrosine-Grb2 signaling during mammalian tissue morphogenesis. Curr Biol. 2001;11:662-670. [PubMed] [DOI] [Cited in This Article: ]

181.	Liu KJ, Arron JR, Stankunas K, Crabtree GR, Longaker MT. Chemical rescue of cleft palate and midline defects in conditional GSK-3beta mice. Nature. 2007;446:79-82. [PubMed] [DOI] [Cited in This Article: ]

182.	Bullock SL, Fletcher JM, Beddington RS, Wilson VA. Renal agenesis in mice homozygous for a gene trap mutation in the gene encoding heparan sulfate 2-sulfotransferase. Genes Dev. 1998;12:1894-1906. [PubMed] [DOI] [Cited in This Article: ]

183.

Keady BT, Samtani R, Tobita K, Tsuchya M, San Agustin JT, Follit JA, Jonassen JA, Subramanian R, Lo CW, Pazour GJ. IFT25 links the signal-dependent movement of Hedgehog components to intraflagellar transport. Dev Cell. 2012;22:940-951. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 159] [Cited by in F6Publishing: 170] [Article Influence: 14.2] [Reference Citation Analysis (0)]

184.	Grashoff C, Aszódi A, Sakai T, Hunziker EB, Fässler R. Integrin-linked kinase regulates chondrocyte shape and proliferation. EMBO Rep. 2003;4:432-438. [PubMed] [DOI] [Cited in This Article: ]

185.

Sohaskey ML, Yu J, Diaz MA, Plaas AH, Harland RM. JAWS coordinates chondrogenesis and synovial joint positioning. Development. 2008;135:2215-2220. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 37] [Cited by in F6Publishing: 38] [Article Influence: 2.4] [Reference Citation Analysis (0)]

186.

Jacoby M, Cox JJ, Gayral S, Hampshire DJ, Ayub M, Blockmans M, Pernot E, Kisseleva MV, Compère P, Schiffmann SN. INPP5E mutations cause primary cilium signaling defects, ciliary instability and ciliopathies in human and mouse. Nat Genet. 2009;41:1027-1031. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 269] [Cited by in F6Publishing: 273] [Article Influence: 18.2] [Reference Citation Analysis (0)]

187.

Brugmann SA, Allen NC, James AW, Mekonnen Z, Madan E, Helms JA. A primary cilia-dependent etiology for midline facial disorders. Hum Mol Genet. 2010;19:1577-1592. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 113] [Cited by in F6Publishing: 109] [Article Influence: 7.8] [Reference Citation Analysis (0)]

188.

Song Z, Liu C, Iwata J, Gu S, Suzuki A, Sun C, He W, Shu R, Li L, Chai Y. Mice with Tak1 deficiency in neural crest lineage exhibit cleft palate associated with abnormal tongue development. J Biol Chem. 2013;288:10440-10450. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 42] [Cited by in F6Publishing: 45] [Article Influence: 4.1] [Reference Citation Analysis (0)]

189.

Yumoto K, Thomas PS, Lane J, Matsuzaki K, Inagaki M, Ninomiya-Tsuji J, Scott GJ, Ray MK, Ishii M, Maxson R. TGF-β-activated kinase 1 (Tak1) mediates agonist-induced Smad activation and linker region phosphorylation in embryonic craniofacial neural crest-derived cells. J Biol Chem. 2013;288:13467-13480. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 58] [Cited by in F6Publishing: 62] [Article Influence: 5.6] [Reference Citation Analysis (0)]

190.

Kowalczyk MS, Hughes JR, Babbs C, Sanchez-Pulido L, Szumska D, Sharpe JA, Sloane-Stanley JA, Morriss-Kay GM, Smoot LB, Roberts AE. Nprl3 is required for normal development of the cardiovascular system. Mamm Genome. 2012;23:404-415. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 30] [Cited by in F6Publishing: 28] [Article Influence: 2.3] [Reference Citation Analysis (0)]

191.	Ferrante MI, Zullo A, Barra A, Bimonte S, Messaddeq N, Studer M, Dollé P, Franco B. Oral-facial-digital type I protein is required for primary cilia formation and left-right axis specification. Nat Genet. 2006;38:112-117. [PubMed] [DOI] [Cited in This Article: ]

192.

Lu S, Lu LY, Liu MF, Yuan QJ, Sham MH, Guan XY, Huang JD. Cerebellar defects in Pdss2 conditional knockout mice during embryonic development and in adulthood. Neurobiol Dis. 2012;45:219-233. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 27] [Cited by in F6Publishing: 29] [Article Influence: 2.2] [Reference Citation Analysis (0)]

193.	Keller P, Tremml G, Rosti V, Bessler M. X inactivation and somatic cell selection rescue female mice carrying a Piga-null mutation. Proc Natl Acad Sci USA. 1999;96:7479-7483. [PubMed] [DOI] [Cited in This Article: ]

194.

Kinoshita M, Era T, Jakt LM, Nishikawa S. The novel protein kinase Vlk is essential for stromal function of mesenchymal cells. Development. 2009;136:2069-2079. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 31] [Cited by in F6Publishing: 32] [Article Influence: 2.1] [Reference Citation Analysis (0)]

195.

Imuta Y, Nishioka N, Kiyonari H, Sasaki H. Short limbs, cleft palate, and delayed formation of flat proliferative chondrocytes in mice with targeted disruption of a putative protein kinase gene, Pkdcc (AW548124). Dev Dyn. 2009;238:210-222. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 37] [Cited by in F6Publishing: 44] [Article Influence: 2.9] [Reference Citation Analysis (0)]

196.

Yang T, Jia Z, Bryant-Pike W, Chandrasekhar A, Murray JC, Fritzsch B, Bassuk AG. Analysis of PRICKLE1 in human cleft palate and mouse development demonstrates rare and common variants involved in human malformations. Mol Genet Genomic Med. 2014;2:138-151. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 26] [Cited by in F6Publishing: 24] [Article Influence: 2.4] [Reference Citation Analysis (0)]

197.	Ng JM, Vrieling H, Sugasawa K, Ooms MP, Grootegoed JA, Vreeburg JT, Visser P, Beems RB, Gorgels TG, Hanaoka F. Developmental defects and male sterility in mice lacking the ubiquitin-like DNA repair gene mHR23B. Mol Cell Biol. 2002;22:1233-1245. [PubMed] [DOI] [Cited in This Article: ]

198.

Jin YR, Turcotte TJ, Crocker AL, Han XH, Yoon JK. The canonical Wnt signaling activator, R-spondin2, regulates craniofacial patterning and morphogenesis within the branchial arch through ectodermal-mesenchymal interaction. Dev Biol. 2011;352:1-13. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 58] [Cited by in F6Publishing: 64] [Article Influence: 4.9] [Reference Citation Analysis (0)]

199.	Nam JS, Park E, Turcotte TJ, Palencia S, Zhan X, Lee J, Yun K, Funk WD, Yoon JK. Mouse R-spondin2 is required for apical ectodermal ridge maintenance in the hindlimb. Dev Biol. 2007;311:124-135. [PubMed] [DOI] [Cited in This Article: ]

200.

Insolera R, Shao W, Airik R, Hildebrandt F, Shi SH. SDCCAG8 regulates pericentriolar material recruitment and neuronal migration in the developing cortex. Neuron. 2014;83:805-822. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 40] [Cited by in F6Publishing: 40] [Article Influence: 4.0] [Reference Citation Analysis (0)]

201.	Wojcik SM, Katsurabayashi S, Guillemin I, Friauf E, Rosenmund C, Brose N, Rhee JS. A shared vesicular carrier allows synaptic corelease of GABA and glycine. Neuron. 2006;50:575-587. [PubMed] [DOI] [Cited in This Article: ]

202.

Oh WJ, Westmoreland JJ, Summers R, Condie BG. Cleft palate is caused by CNS dysfunction in Gad1 and Viaat knockout mice. PLoS One. 2010;5:e9758. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 16] [Cited by in F6Publishing: 18] [Article Influence: 1.3] [Reference Citation Analysis (0)]

203.

Yang X, Kilgallen S, Andreeva V, Spicer DB, Pinz I, Friesel R. Conditional expression of Spry1 in neural crest causes craniofacial and cardiac defects. BMC Dev Biol. 2010;10:48. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 28] [Cited by in F6Publishing: 31] [Article Influence: 2.2] [Reference Citation Analysis (0)]

204.	Welsh IC, Hagge-Greenberg A, O’Brien TP. A dosage-dependent role for Spry2 in growth and patterning during palate development. Mech Dev. 2007;124:746-761. [PubMed] [DOI] [Cited in This Article: ]

205.	Alkuraya FS, Saadi I, Lund JJ, Turbe-Doan A, Morton CC, Maas RL. SUMO1 haploinsufficiency leads to cleft lip and palate. Science. 2006;313:1751. [PubMed] [DOI] [Cited in This Article: ]

206.

Qu X, Pan Y, Carbe C, Powers A, Grobe K, Zhang X. Glycosaminoglycan-dependent restriction of FGF diffusion is necessary for lacrimal gland development. Development. 2012;139:2730-2739. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 37] [Cited by in F6Publishing: 44] [Article Influence: 3.7] [Reference Citation Analysis (0)]

207.

Cui C, Chatterjee B, Lozito TP, Zhang Z, Francis RJ, Yagi H, Swanhart LM, Sanker S, Francis D, Yu Q. Wdpcp, a PCP protein required for ciliogenesis, regulates directional cell migration and cell polarity by direct modulation of the actin cytoskeleton. PLoS Biol. 2013;11:e1001720. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 85] [Cited by in F6Publishing: 81] [Article Influence: 7.4] [Reference Citation Analysis (0)]

208.

Li SW, Prockop DJ, Helminen H, Fässler R, Lapveteläinen T, Kiraly K, Peltarri A, Arokoski J, Lui H, Arita M. Transgenic mice with targeted inactivation of the Col2 alpha 1 gene for collagen II develop a skeleton with membranous and periosteal bone but no endochondral bone. Genes Dev. 1995;9:2821-2830. [PubMed] [Cited in This Article: ]

209.	Costell M, Gustafsson E, Aszódi A, Mörgelin M, Bloch W, Hunziker E, Addicks K, Timpl R, Fässler R. Perlecan maintains the integrity of cartilage and some basement membranes. J Cell Biol. 1999;147:1109-1122. [PubMed] [DOI] [Cited in This Article: ]

210.	Arikawa-Hirasawa E, Watanabe H, Takami H, Hassell JR, Yamada Y. Perlecan is essential for cartilage and cephalic development. Nat Genet. 1999;23:354-358. [PubMed] [DOI] [Cited in This Article: ]

211.

Masago Y, Hosoya A, Kawasaki K, Kawano S, Nasu A, Toguchida J, Fujita K, Nakamura H, Kondoh G, Nagata K. The molecular chaperone Hsp47 is essential for cartilage and endochondral bone formation. J Cell Sci. 2012;125:1118-1128. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 39] [Cited by in F6Publishing: 39] [Article Influence: 3.3] [Reference Citation Analysis (0)]

212.

Rainger J, van Beusekom E, Ramsay JK, McKie L, Al-Gazali L, Pallotta R, Saponari A, Branney P, Fisher M, Morrison H. Loss of the BMP antagonist, SMOC-1, causes Ophthalmo-acromelic (Waardenburg Anophthalmia) syndrome in humans and mice. PLoS Genet. 2011;7:e1002114. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 68] [Cited by in F6Publishing: 71] [Article Influence: 5.5] [Reference Citation Analysis (1)]