Extracellular Matrix Remodeling During Palate Development

Figures & data

Figure 1. ECM remodeling during palate development.

Table 1. Cleft palate-related ECM gene mutation in human and mice.

Gene	Protein	Human Disease	Cleft palate related Clinal features	References	Mouse mutation	Mouse mutation phenotypes	References
COL2A1	Col II	Stickler syndrome type 1 (OMIM 108300)	Cleft palate or bifid uvula,	^Citation26,Citation109-Citation111	Transgenic Del1 mice carrying six copies of with COL2A1 (Del) mutation with a 150-bp deletion containing the 45-bp exon 7 and intro7:	Craniofacial ossification retarded; reduced cartilage and bone growth; cleft palate;	^Citation38
		Kniest dysplasia (OMIM 156550)	Cleft palate	^Citation111	Transgenic mice with targeted inactivation of the COL2A1 gene	No endochondral bone or epiphyseal growth plate in long bones with normal membranous and periosteal skeleton	^Citation34
		Platyspondyly lethal skeletal dysplasia (OMIM 151210)	No cleft palate	^Citation111	ENU induced mutation has a G to A transition at Chromosome 15:97815207, which causes a premature stop codon at amino acid 645	Cleft palate; shortened nose	^Citation112
COL11A1	Col XI	Stickler syndrome type 2 (OMIM 604841)	Cleft palate	^Citation110	Deletion of a cytidine residue about 570 nt downstream of the translation initiation codon in COL11A1 (cho) mRNA causes a reading frame shift and introduces a premature stop codon	Cleft palate, shortened head and mandible, short limbs, protruding tongue	^Citation39,Citation40
		Marshall syndrome (OMIM 154780)	Cleft palate	^Citation26
COL11A2	Col XI	Stickler syndrome type 3: (OMIM 184480)	Cleft palate	^Citation110	Full-length Col11a2 chain was unable to occur because of the presence of premature termination codons	NO cleft palate; Hearing loss, smaller size, shorter snout, skeletal abnormalities including abnormal cranium morphology and long bone epiphyseal plate	^Citation41,Citation42
		Nance-Insley syndrome (OMIM 215150)	Cleft palate	^Citation41
FN1	Fibronectin	NR			Conditional knock out FN1 in cranial neural crest cells	Cleft palate, abnormal cardiac morphogenesis, thymus development defects	^Citation48
					Conditional knock out FN1 in mesoderm cells	Cleft palate, abnormal cardiac morphogenesis, thymus development defects, edema, etc.	^Citation47
TNXB	Tenascin-X	Tenascin-X deficiency (OMIM 606408)	Bifid uvula	^Citation55,Citation56,Citation113,Citation114	NR
ACAN	Aggrecan	NR			Gene mutation in ACAN: cmd/cmd (cartilage matrix defieciency), 7-bp deletion in exon 5; cmd-Bc, spontaneous mutation, complete loss of exons 2-18	Cleft palate, short limbs, tail, and snout	^Citation115,Citation116
VCAN	Versican	NR			Haploinsufficiendy of Versican in Adamts20 mutant mice (Vcan^hdf/+;Adamts20^bt/bt)	65% mutant exhibited cleft palate	^Citation12

NR, not reported.

Table 2. ECM molecules expression, function, and remodeling pattern during palatogenesis.

		Expression pattern in the palate			Functional roles during palatogenesis			Remodeling during palatogenesis
ECM component	Subtype	Location	Detection methods	Species/References	Potential mechanism	Potential function	References	Abnormal remodeling	Detection methods	References
Collagens (Col)	Col I	Before palatal elevation: Epithelial basement membrane and palatal mesenchyme (stronger on the nasal side than the oral side in the middle and posterior palate) After palatal elevation: Mesenchyme around the bone	IHC	Mouse^Citation7,Citation20-Citation23,Citation117	Main structure protein	Build up palate infrastructure	^Citation7	Col I is downregulated in the palatal shelves of Foxf2^−/- mouse embryos	IHC	^Citation15
								Col I and its degrading enzyme MMP 13 are downregulated in T1KO mice	qRT-PCR, WB, IHC	^Citation14
			qRT-PCR, dot blot	Human:^Citation24				Col I synthesis by palatal mesenchymal cells can be induced by TGFβ1 and inhibited by MiR-17-92 clusters	qRT-PCR, WB	^Citation16
								Col I synthesis by palatal mesenchymal cells can be induced by TGFβ2	IHC	^Citation7
	Col II	After the palatal shelf elevation: A few palatal mesenchymal cells	IHC	Mouse:^Citation8	Main cartilage ECM	Palatal mesenchyme osteogenic/chondrogenic fate determination	^Citation8	Enhanced FGF8 signaling causes strong expression of Col II in palatal mesenchymal cells	IHC	^Citation8
	Col III	Before palatal elevation: Epithelial basement membrane and palatal mesenchyme	IHC	Mouse:^Citation23,Citation25	Main structure protein	Build up palate infrastructure	^Citation23	Col III synthesis by palatal mesenchymal cells can be induced by TGFβ1 and inhibited by MiR-17-92 clusters	qRT-PCR, WB	^Citation16
			qRT-PCR, dot blot	Human:^Citation24
	Col IV	Epithelial basement membrane	IHC	^Citation10,Citation17,Citation20,Citation25	NR			Col IV expression in the palate is reduced in the Tgf-β3 mutant and can be re-induced by Tgf-β3	IHC	^Citation17
Fibronectin		Before palate elevation: Palatal mesenchyme and around MEE, with strong expression around the bulging MEE cells After palate elevation: MES	IHC, ISH	^Citation6,Citation17,Citation20-Citation23	NR			Absent in MEE cells and apical surface in the Tgf-β3 mutant palate and can be re-induced by Tgf-β3; Downregulated in BMP 7 homozygous palate; EDA domain reduced in Foxf2^−/- palatal shelves; Inhibited by retinoid acid in a dose-dependent manner.	IHC, qRT-PCR, WB	^Citation6,Citation15,Citation17,Citation49
Fibrillins	Fibrillin-1	Weakly expressed in the palatal mesenchyme only before palatal shelf elevation	IHC	^Citation6	Compose microfibirls and activate Tgf-β	Palatal fusion	^Citation6	NR
	Fibrillin-2	Before palatal shelf elevation: enriched in the nasal side of palatal mesenchyme After palatal elevation: increased and expanded around MEE cells and in the oral side of palatal mesenchyme	IHC	^Citation6				Inhibited by retinoid acid in a dose-dependent manner	qRT-PCR	^Citation49
Tenascins	Tenascin-C	Before palatal elevation: in the mesenchyme close to the nasal and distal surface of the shelf; After palatal elevation: accumulated in the mesenchyme close to the MES	IHC, ISH	^Citation1,Citation6,Citation53	NR			Reduced in Foxf2^−/- mutant palatal shelves Inhibited by retinoid acid in a dose-dependent manner	qRT-PCR	^Citation15,Citation49
	Tenascin-W	Before palatal elevation: weekly expressed in the proximal-nasal quadrant of the vertical shelves; After palatal elevation: restricted to the dorsal mesenchyme around the MES, corresponding to the future osteogenic domains of hard palate	IHC, ISH	^Citation1,Citation6,Citation53	NR			Diminished in the palatal shelves of BMP7^−/- palatal shelves; BMP7 induce Tenascin-W production in embryonic fibroblasts in vitro	ISH, WB	^Citation6
Periostin		In the anterior palate (hard palate), periostin is expressed in the mesenchyme on the oral side and part of basal membrane; Intensified around MEE cells in palate fusing process; highly expressed in the entire posterior palate (soft palate)	IHC, ISH	^Citation7,Citation53,Citation62	May help to determine soft palate formation	Soft palate formation	^Citation7	TGFβ2 induce periostin production in cultured palate shelves.	IHC	^Citation7
Laminin	Laminin 5	Discontinuously in the basement membrane and intercellularly in MEE cells	IHC	^Citation17,Citation25	NR			Becomes continuous in the basement membrane under MEE cells in the Tgf-β3 mutant palate	IHC	^Citation17
Proteoglycans	CSPGs	CS chains Before the palatal shelf elevation: palatal mesenchyme; During the palatal shelf elevation and the palatal shelf fusion: palatal mesenchyme, transiently upregulated on apical surface of MEE surface; After the palatal shelf fusion: Palatal mesenchyme around the bone	IHC	Mouse:^Citation11,Citation14,Citation18	Hold up water; Bind other ECM molecules; Modify TGFβ signaling	Palatal growth, expansion, elevation and adhesion	^Citation12-Citation14,Citation118	Reduced in TGFβ3^−/- mutant the palatal shelf mesenchyme and disappeared in mutant MEE surface; TGFβ3 induce CSPGs production in cultured palate shelf MEE cells.	IHC	^Citation18
		Versican Before the palatal shelf elevation: Palatal mesenchyme (stronger in nasal/medial and tip than oral/lateral palate) During the palatal shelf elevation and the palatal shelf fusion: Palatal mesenchyme (stronger in nasal/medial and tip than oral/lateral palate, although increased in oral/lateral part), transiently upregulated on apical surface of MEE surface; After the palatal shelf fusion: Decreased in palatal mesenchyme	IHC	^Citation11,Citation12				Cleaved versican decreased in Adamts9;^±Adamts20^bt/bt palatal shelves	IHC	^Citation12
		Biglycan/Decorin palatal mesenchymal cells at different palate development stages (Decorin restricted to the nasal side); peaked in MEE cells as the palatal shelf adhered	IHC, ISH, qRT-PCR	^Citation13,Citation76,Citation77				Disappeared in the MES of TGFβrI kinase inhibitor (SB431542)–treated palates; Decorin are unable to downregulate in the mesenchyme when palatal shelves are elevating; Decorin are downregulated in ectopic Hh signaling palatal shelves	IHC, ISH	^Citation13,Citation76,Citation77
	HSPGs	Before the palatal shelf elevation: Epithelial basement membrane and anterior palatal mesenchyme; During the palatal shelf elevation and the palatal shelf fusion: Epithelial basement membrane (stronger in the oral/lateral side than the nasal/medial side) and the tip of the whole palatal mesenchyme; After the palatal shelf fusion: Epithelial basement membrane (stronger in the oral side than the nasal side); gradually disappear from the palatal mesenchyme; Around vessel basement membrane at all stages	IHC	^Citation11,Citation25
	KSPGs	Lumican Restricted to the nasal mesenchyme of the palate	ISH	^Citation77				Lumican are downregulated in ectopic Hh signaling palatal shelves	ISH	^Citation77
	HA	Before the palatal shelf elevation: palatal mesenchyme (anterior/mid-part stronger than anterior-most and posterior palate; stronger in the nasal/medial side than the oral/lateral side)	IHC	^Citation9,Citation11,Citation78	Retain water	Palatal shelf elevation	^Citation1,Citation9-Citation11	Reduced in Fgfr2^C342Y, Pax9 and Golgb1 mutant palatal shelves; HA synthase Has 1, 2, and 3 disrupted in Tgf-β3 mutant shelves.	IHC	^Citation9,Citation49,Citation88,Citation89

Table 3. MMP associated with palate development.

		Expression pattern in the palate				Mouse mutant associated with cleft palate
Extracellular metalloproteinases	Subtype/alternative name	Location	Detection methods	References	ECM substrates during palate development	Mouse mutants	Defects	References
MMPs	MMP-1/Collagenase-1	Unknown	qRT-PCR	^Citation24	NR	NR
	MMP-2/Gelatinase A	Before palate shelf elevation: in the palatal mesenchyme and basement membrane, intensified gradually in the nasal-medial part. During the palatal shelf elevation and the palatal shelf fusion: intensified gradually in the tip and nasal-medial part and MES After the palatal shelf fusion: strong in palatal mesenchyme around MES.	qRT-PCR, IHC, ISH	^Citation1-Citation3,Citation24,Citation100,Citation105	Cleaves type I collagen	NR
	MMP-3	Extensively expressed in palatal mesenchyme, transiently upregulated in a subset of nasal palatal epithelial cells.	IHC	^Citation100,Citation102,Citation106	NR	NR
	MMP-9/Gelatinase B	Extensively expressed in palatal mesenchyme, transiently upregulated while palatal shelves elevating and fusing.	qRT-PCR, IHC, ISH	Human and mouse:^Citation24,Citation102,Citation104	Cleaves laminin	NR
	MMP13	Before palate shelf elevation: in the palatal mesenchyme and basement membrane, intensified gradually in the nasal-medial part. During the palatal shelf elevation and the palatal shelf fusion: intensified gradually in the tip and nasal-medial part and MES After the palatal shelf fusion: still strong in the nasal-medial mesenchyme and MES but decreased in other area.	IHC, ISH	Mouse^Citation100,Citation105,Citation119	NR	NR
	MMP-14/Membrane Type 1-MMP (MT1-MMP)	Highly in MEE	IHC, ISH	^Citation105	NR	Double knockout of MMP-14 and −16	80% of double null of MMP-14 and −16 have a cleft palate	^Citation107
	MMP-16/Membrane Type 3-MMP (MT3-MMP)	Unknown			NR	Double knockout of MMP-14 and −16	80% of double null of MMP-14 and −16 have a cleft palate	^Citation107
	MMP-25	The tips of palatal epithelium and mesenchyme	IHC, ISH	^Citation108	NR	NR
TIMPs	TIMP-1	Before palate shelf elevation: in the central and maxillary region of palatal mesenchyme During the palatal shelf elevation and the palatal shelf fusion: intensified gradually in the tip and nasal-medial part and MES; palatal basement membrane After the palatal shelf fusion: strong in the nasal-medial mesenchyme and MES but decreased in other area.	IHC	^Citation100	NR	NR
	TIMP-2	Before palate shelf elevation: in the central and maxillary region of palatal mesenchyme During the palatal shelf elevation and the palatal shelf fusion: intensified within palatal mesenchyme; palatal basement membrane After the palatal shelf fusion: strong in the nasal-medial mesenchyme and future osteogenic sites.	IHC	^Citation100	NR	NR
	TIMP-3	Palatal epithelium, transiently expressed in mid-oral and ventral-medial mesenchyme.	IHC	^Citation100	NR	NR
	TIMP-4	Oral mucosa	IHC	^Citation104	NR	NR
ADAMTS	ADAMTS9	Palatal capillary endothelium	ISH	^Citation12	Versican	Haploinsufficiendy of Adamts9 in Adamts20 mutant mice (Adamts9^±;Adamts20^bt/bt)	Complete cleft palate	^Citation12
	ADAMTS20	Palatal mesenchyme	ISH	^Citation12

NR, not reported.

IHC, immunohistochemical staining.

ISH, in situ hybridization.

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