Molecular basis of cleft palates in mice

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)
Acvr2a	Activin A receptor, type IIA	[34]	1102581	nr	nr
Bmp4	Bone morphogenetic protein 4	[35]	1112262	Microphthalmia, syndromic 6	r
				Orofacial cleft 11
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)				Polyposis syndrome
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
				LADD syndrome
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)				Hypereosinophilic syndrome, idiopathic, resistant to imatinib
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)
Tgfbr2	Transforming growth factor, beta receptor II	[12,58]	1190182	Loeys-Dietz syndrome, type 2	r
(Wnt1-Cre-, and KRT14-Cre-mediated ablation)
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)
Itgb1	Integrin beta 1	[67]	1135630	nr	nr
(Col2a1-Cre-mediated ablation)
Itgb8	Integrin beta 8	[68]	1604160	nr	nr
Jag1	Jagged1	[69]	2601920	Alagille syndrome	nr
(Wnt1-Cre-mediated ablation)
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
				Brachydactyly, type B1
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
				Single median maxillary central incisor
Smo/Smoh	Smoothened, frizzled class receptor	[78]	1601500	Basal cell carcinoma, somatic	nr
(Wnt1-Cre-mediated ablation)
Tctn2	Tectonic family member 2	[79]	1613846	Meckel syndrome 8	r
Wls/Gpr177	Wntless homolog (Drosophila)	[80]	1611514	nr	nr
(Wnt1-Cre-mediated ablation)
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)
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
				Myelodysplastic syndrome, somatic
Barx1	BarH-like homeobox 1	[89]	1603260	nr	nr
Cdc42	Cell division cycle 42	[90]	1116952	nr	nr
(Prrx1-Cre-mediated ablation)
Chd7	Chromodomain helicase DNA binding protein 7	[91,92]	1608892	CHARGE syndrome	r
(heterozygotes) (Wnt1-Cre-mediated ablation)				Hypogonadotropic hypogonadism 5 with or without anosmia
Cited2	CBP/p300-interacting transactivator, with Glu/Asp-rich C-terminal domain, 2	[93]	1602937	Atrial septal defect 8	nr
				Ventricular septal defect 2
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)
Foxe1/Titf2/Fkhl15	Forkhead box E1	[102]	1602617	Bamforth-Lazarus syndrome	r
				Nonsyndromic orofacial clefting
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
				Holoprosencephaly-9
Gli3	GLI family zinc finger 3	[105]	1165240	Greig cephalopolysyndactyly syndrome	r
				Pallister-Hall syndrome
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
				Microtia, hearing impairment, and cleft palate (AR)
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)				Mental retardation, stereotypic movements, epilepsy, and/or cerebral malformations
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
				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
				Liebenberg syndrome
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
				Left ventricular noncompaction 8
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)
				Holoprosencephaly type 7
Pygo2	Pygopus 2	[131]	1606903	nr	nr
(CMV-Cre-mediated ablation)
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
				Myhre syndrome
Smad7	SMAD family member 7	[139]	1602932	uc	nr
Snai2	Snail family zinc finger 2	[140]	1602150	Piebaldism	nr
				Waardenburg syndrome, type 2D
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)
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
				submucous cleft palate (SMCP)
Tcof1	Treacher Collins-Franceschetti syndrome 1	[150]	1606847	Treacher-Collins syndrome	r
(heterozygous)
Tfap2A	Transcription factor AP-2 alpha	[151]	1107580	Branchio-oculo-facial syndrome	r
(Wnt1-Cre-mediated ablation)
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
				Mental retardation and microcephaly with pontine and cerebellar hypoplasia
Cdkn1c/p57kip2	Cyclin-dependent kinase inhibitor 1C	[161,162]	1600856	Beckwith-Wiedemann syndrome	r
				IMAGe syndrome
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)
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
				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)
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
				Mental retardation, truncal obesity, retinal dystrophy, and micropenis
Kif3a	Kinesin family member 3A	[187]	1604683	nr	nr
(Wnt1-Cre-mediated ablation)
Map3k7/Tak1	Mitogen-activated protein kinase kinase kinase 7	[188,189]	1602614	nr	nr
(Wnt1-Cre-mediated ablation)
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
				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)
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)
Pkdcc/Vlk	Protein kinase domain containing, cytoplasmic	[194,195]	1614150	nr	nr
(Sox2-Cre-mediated ablation)
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
				Senior-Loken syndrome 7
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)
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)
Ugdh	UDP-glucose dehydrogenase	[206]	1603370	nr	nr
(Wnt1-Cre-mediated ablation)
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
				Schwartz-Jampel syndrome, type 1
Serpinh1/Hsp47	Serpine peptidase inhibitor, clade H, member 1	[211]	1600943	Osteogenesis imperfecta, type X	nr
(Col2a1-Cre-mediated ablation)
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.

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.