Mice with Tak1 Deficiency in Neural Crest Lineage Exhibit Cleft Palate Associated with Abnormal Tongue Development

Zhang, Song; Liu, Chao; Iwata, Junichi; Gu, Shaohua; Suzuki, Akiko; Sun, Cheng; Wang, He; Shu, Rong; Li, Lü; Chai, Yang; Chen, Yiping

doi:10.1074/jbc.m112.432286

Cited by 52 publications

(54 citation statements)

References 53 publications

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“…For histology, serial sections of 7 m were stained with hematoxylin and eosin. The tongue heights were measured on the basis of serial coronal sections of embryonic heads between E13.5 and E16.5 as described previously (8). Frontal sections through palatal shelves were selected from the anterior, middle, and posterior regions, with the middle region consisting of sections through the maxillary first molar tooth buds.…”

Section: Methodsmentioning

confidence: 99%

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Ablation of the Sox11 Gene Results in Clefting of the Secondary Palate Resembling the Pierre Robin Sequence

Huang

Xiao

Bao

et al. 2016

Journal of Biological Chemistry

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Mouse gene inactivation has shown that the transcription factor Sox11 is required for mouse palatogenesis. However, whether Sox11 is primarily involved in the regulation of palatogenesis still remains elusive. In this study, we explored the role of Sox11 in palatogenesis by analyzing the developmental mechanism in cleft palate formation in mutants deficient in Sox11. Sox11 is expressed both in the developing palatal shelf and in the surrounding structures, including the mandible. We found that cleft palate occurs only in the mutant in which Sox11 is directly deleted. As in the wild type, the palatal shelves in the Sox11 mutant undergo outgrowth in a downward direction and exhibit potential for fusion and elevation. However, mutant palatal shelves encounter clefting, which is associated with a malpositioned tongue that results in physical obstruction of palatal shelf elevation at embryonic day 14.5 (E14.5). We found that loss of Sox11 led to reduced cell proliferation in the developing mandibular mesenchyme via Cyclin D1, leading to mandibular hypoplasia, which blocks tongue descent. Extensive analyses of gene expression in Sox11 deficiency identified FGF9 as a potential candidate target of Sox11 in the modulation of cell proliferation both in the mandible and the palatal shelf between E12.5 and E13.5. Finally we show, using in vitro assays, that Sox11 directly regulates the expression of Fgf9 and that application of FGF9 protein to Sox11-deficient palatal shelves restores the rate of BrdU incorporation. Taken together, the palate defects presented in the Sox11 loss mutant mimic the clefting in the Pierre Robin sequence in humans.

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Section: Methodsmentioning

confidence: 99%

“…For in vitro palatal shelf elevation assays, roller cultures were performed essentially as described previously (8). The embryonic head with either the mandible or tongue removed was placed into a 20-ml glass culture tube containing 2 ml of medium.…”

Section: Methodsmentioning

confidence: 99%

Ablation of the Sox11 Gene Results in Clefting of the Secondary Palate Resembling the Pierre Robin Sequence

Huang

Xiao

Bao

et al. 2016

Journal of Biological Chemistry

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“…We accomplished this by using pMes-Fgf10 transgenic mice, a previously described line in which Cre-dependent excision of a transcriptional stop cassette leads to expression of fulllength mouse Fgf10 under the control of the chick β-actin promoter (Song et al, 2013). Using this line, we aimed to induce Fgf10 expression selectively in neuroretina of both control and Chx10-Cre; Lhx2 lox/lox mice (Fig.…”

Section: Fgf Signaling Is Downregulated In Lhx2-deficient Eyesmentioning

confidence: 99%

“…Chx10-Cre (Rowan and Cepko, 2004) mice were a gift from Dr Connie Cepko (Harvard, Boston, MA, USA). pMes-Fgf10 (Song et al, 2013) mice were generously provided by Dr Yang Chai (University of Southern California, Los Angeles, CA, USA). Ai9 (R26-CAG-lox-stop-lox-tdTomato) (Madisen et al, 2010) ;pMes-Fgf10 and Chx10-Cre;Ai9 mice were generated by breeding with subsequent backcrossing.…”

Section: Lhx2mentioning

confidence: 99%

Control of lens development by Lhx2-regulated neuroretinal FGFs

et al. 2016

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Fibroblast growth factor (FGF) signaling is an essential regulator of lens epithelial cell proliferation and survival, as well as lens fiber cell differentiation. However, the identities of these FGF factors, their source tissue and the genes that regulate their synthesis are unknown. We have found that Chx10-Cre;Lhx2 lox/lox mice, which selectively lack Lhx2 expression in neuroretina from E10.5, showed an early arrest in lens fiber development along with severe microphthalmia. These mutant animals showed reduced expression of multiple neuroretina-expressed FGFs and canonical FGFregulated genes in neuroretina. When FGF expression was genetically restored in Lhx2-deficient neuroretina of Chx10-Cre; Lhx2 lox/lox mice, we observed a partial but nonetheless substantial rescue of the defects in lens cell proliferation, survival and fiber differentiation. These data demonstrate that neuroretinal expression of Lhx2 and neuroretina-derived FGF factors are crucial for lens fiber development in vivo.

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“…The formation process of the secondary palatal development, including growth of the palatal shelves, elevation of the palatal shelves, fusion between paired palatal shelves and the disappearance of the midline epithelial seam, is regulated precisely. Disruption at any stage of these steps, involving in growth, elevation or fusion, genetically or environmentally, can cause cleft palate 1) . This malformation can occur in a non-syndromic form or a syndromic form in conjunction with recognized Mendelian or teratogenic malformations 2) .…”

Section: Introductionmentioning

confidence: 99%

Identification of the Differentially Expressed microRNAs Involved in Cleft Palate Induced by Retinoic Acid (RA) in Mouse Model

Wei

Huang

et al. 2018

J. Hard Tissue Biology.

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Identifying the diff erentially expressed miRNAs in cleft palate, in order to study the molecular mechanism in the development and progress of cleft palate. C57BL/6J mice were used to establish the RA induced cleft palate mouse model. Nine pairs of tissues were obtained on embryonic day 15.5 (E15.5). Total RNA was extracted and miRNAs microarray chip was used to screen the miRNAs. Real-time quantitative PCR (RT-qPCR) was used to verify the miRNAs microarray chip results. Cleft palate related genes targeted by the miRNAs were predicted by TargetScan and miRTarBase, and functional annotation clustering of Gene Ontology (GO) term and KEGG signaling pathways in DAVID were used to analysis these target genes. 1265 miRNAs were identifi ed in cleft palate, and among them 31 were diff erentially expressed (p < 0.01, fold change > 1.5), including 17 up-regulated and 14 down-regulated miRNAs in cleft palate. 7 up-regulated miRNAs (mmu-miR181a-5p, mmu-miR-410-3p, mmu-miR-3960, mmu-miR-1224-5p, mmu-miR-3970, mmu-let-7e-5p and mmu-miR-1907) and 3 down-regulated miRNAs (mmu-miR-140-3p, mmu-miR-351-5p and mmu-miR-503-5p) were validated by RT-qPCR, and mmumiR-181a-5p and mmu-miR-410-3p were in concordance with those of miRNAs microarray chip detection. 484 target genes were predicted and proven by TargetScan and miRTarBase. GO term showed that RA-induced cleft palate was associated with enrichments in miRNAs involved in embryo development, osteoblast diff erentiation and so on. KEGG signaling pathways analysis indicated that the diff erentially expressed miRNAs were involved in MAPK, TGFβ and WNT signaling pathways. 10 diff erentially expressed miRNAs in cleft palate have been identifi ed. These miRNAs and their target genes may become new therapeutic targets for cleft palate.

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Mice with Tak1 Deficiency in Neural Crest Lineage Exhibit Cleft Palate Associated with Abnormal Tongue Development

Cited by 52 publications

References 53 publications

Ablation of the Sox11 Gene Results in Clefting of the Secondary Palate Resembling the Pierre Robin Sequence

Ablation of the Sox11 Gene Results in Clefting of the Secondary Palate Resembling the Pierre Robin Sequence

Control of lens development by Lhx2-regulated neuroretinal FGFs

Identification of the Differentially Expressed microRNAs Involved in Cleft Palate Induced by Retinoic Acid (RA) in Mouse Model

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