Deletion of the T-box transcription factor gene, Tbx1, in mice induces differential expression of genes associated with cleft palate in humans

Funato, Noriko; Yanagisawa, Hiromi

doi:10.1016/j.archoralbio.2018.08.001

Cited by 5 publications

(4 citation statements)

References 35 publications

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“…Expression of Pax9 , whose mutations lead to cleft palate and tooth agenesis [ 70 ], is downregulated in the palatal shelves and pharyngeal region of Tbx1 -null embryos [ 34 , 71 ]. In Tbx1 -null palatal shelves, muscle- and bone-related genes are downregulated, whereas neuron- and collagen biosynthesis-related genes are upregulated [ 72 ].…”

Section: Craniofacial Phenotypes Of Dgs/vcfs Mouse Modelsmentioning

confidence: 99%

“…In Tbx1 -null and Tbx1 flox/- ; Mesp1 - Cre embryos, the masseter, pterygoid, and temporalis muscles are intermittently absent [ 78 , 79 ]. Accordingly, muscle-related genes are also downregulated in Tbx1 -null palatal shelves [ 72 ]. Tbx1 acts upstream of critical transcription factors to form branchiomeric muscles.…”

Section: Craniofacial Phenotypes Of Dgs/vcfs Mouse Modelsmentioning

confidence: 99%

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Craniofacial Phenotypes and Genetics of DiGeorge Syndrome

Funato

2022

JDB

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The 22q11.2 deletion is one of the most common genetic microdeletions, affecting approximately 1 in 4000 live births in humans. A 1.5 to 2.5 Mb hemizygous deletion of chromosome 22q11.2 causes DiGeorge syndrome (DGS) and velocardiofacial syndrome (VCFS). DGS/VCFS are associated with prevalent cardiac malformations, thymic and parathyroid hypoplasia, and craniofacial defects. Patients with DGS/VCFS manifest craniofacial anomalies involving the cranium, cranial base, jaws, pharyngeal muscles, ear-nose-throat, palate, teeth, and cervical spine. Most craniofacial phenotypes of DGS/VCFS are caused by proximal 1.5 Mb microdeletions, resulting in a hemizygosity of coding genes, microRNAs, and long noncoding RNAs. TBX1, located on chromosome 22q11.21, encodes a T-box transcription factor and is a candidate gene for DGS/VCFS. TBX1 regulates the fate of progenitor cells in the cranial and pharyngeal apparatus during embryogenesis. Tbx1-null mice exhibit the most clinical features of DGS/VCFS, including craniofacial phenotypes. Despite the frequency of DGS/VCFS, there has been a limited review of the craniofacial phenotypes of DGC/VCFS. This review focuses on these phenotypes and summarizes the current understanding of the genetic factors that impact DGS/VCFS-related phenotypes. We also review DGS/VCFS mouse models that have been designed to better understand the pathogenic processes of DGS/VCFS.

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Section: Craniofacial Phenotypes Of Dgs/vcfs Mouse Modelsmentioning

confidence: 99%

Section: Craniofacial Phenotypes Of Dgs/vcfs Mouse Modelsmentioning

confidence: 99%

Craniofacial Phenotypes and Genetics of DiGeorge Syndrome

Funato

2022

JDB

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“…Mutations in the EYA transcriptional coactivator and phosphatase 4 (Eya4) and Fbxo11, which cause delayed or failed mesenchyme regression during ME cavitation, have also been associated with OM (Depreux et al, 2008;Del-Pozo et al, 2019a). T-box transcription factor 1 (Tbx1) deficiency disrupts the function of the muscles that control ET function (Fuchs et al, 2015;Funato and Yanagisawa, 2018), while OM model mice carrying mutations in the cell adhesion protein Cdh11 display ME cavitation defects (Kiyama et al, 2018). Further study of many of previous identified genes in mouse models is needed to elucidate the cellular and molecular mechanism of these genes in OM.…”

Section: Genes Involved In Anti-inflammatory Responses In Ommentioning

confidence: 99%

Current Understanding of Host Genetics of Otitis Media

Geng¹,

Wang²,

Chen³

et al. 2020

Front. Genet.

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The pathogenesis of otitis media (OM), an inflammatory disease of the middle ear (ME), involves interplay between many different factors, including the pathogenicity of infectious pathogens, host immunological status, environmental factors, and genetic predisposition, which is known to be a key determinant of OM susceptibility. Animal models and human genetics studies have identified many genes and gene variants associated with OM susceptibility: genes that encode components of multiple signaling pathways involved in host immunity and inflammatory responses of the ME mucosa; genes involved in cellular function, such as mucociliary transport, mucin production, and mucous cell metaplasia; and genes that are essential for Eustachian tube (ET) development, ME cavitation, and homeostasis. Since our last review, several new mouse models with mutations in genes such as CCL3, IL-17A, and Nisch have been reported. Moreover, genetic variants and polymorphisms in several genes, including FNDC1, FUT2, A2ML1, TGIF1, CD44, and IL1-RA variable number tandem repeat (VNTR) allele 2, have been identified as being significantly associated with OM. In this review, we focus on the current understanding of the role of host genetics in OM, including recent discoveries and future research prospects. Further studies on the genes identified thus far and the discovery of new genes using advanced technologies such as gene editing, next generation sequencing, and genome-wide association studies, will advance our understanding of the molecular mechanism underlying the pathogenesis of OM and provide new avenues for early screening and developing effective preventative and therapeutic strategies to treat OM.

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“…Among these genes, additional myosin family members are included (MYH15, MYH2, MYH3, MYH4, MYO18B, MYO15A). In Tbx1-knockout palatal shelves, a gene profile analysis showed that myosin heavy chain 3 (Myh3) and nebulin (Neb) were downregulated [31]. Other genes included in the GO:0008092 list have been related in some way to the OFC onset.…”

mentioning

confidence: 99%

Ultra-Rare Variants Identify Biological Pathways and Candidate Genes in the Pathobiology of Non-Syndromic Cleft Palate Only

et al. 2023

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In recent decades, many efforts have been made to elucidate the genetic causes of non-syndromic cleft palate (nsCPO), a complex congenital disease caused by the interaction of several genetic and environmental factors. Since genome-wide association studies have evidenced a minor contribution of common polymorphisms in nsCPO inheritance, we used whole exome sequencing data to explore the role of ultra-rare variants in this study. In a cohort of 35 nsCPO cases and 38 controls, we performed a gene set enrichment analysis (GSEA) and a hypergeometric test for assessing significant overlap between genes implicated in nsCPO pathobiology and genes enriched in ultra-rare variants in our cohort. GSEA highlighted an enrichment of ultra-rare variants in genes principally belonging to cytoskeletal protein binding pathway (Probability Density Function corrected p-value = 1.57 × 10−4); protein-containing complex binding pathway (p-value = 1.06 × 10−2); cell adhesion molecule binding pathway (p-value = 1.24 × 10−2); ECM-receptor interaction pathway (p-value = 1.69 × 10−2); and in the Integrin signaling pathway (p-value = 1.28 × 10−2). Two genes implicated in nsCPO pathobiology, namely COL2A1 and GLI3, ranked among the genes (n = 34) with nominal enrichment in the ultra-rare variant collapsing analysis (Fisher’s exact test p-value < 0.05). These genes were also part of an independent list of genes highly relevant to nsCPO biology (n = 25). Significant overlap between the two sets of genes (hypergeometric test p-value = 5.86 × 10−3) indicated that enriched genes are likely to be implicated in physiological palate development and/or the pathological processes of oral clefting. In conclusion, ultra-rare variants collectively impinge on biological pathways crucial to nsCPO pathobiology and point to candidate genes that may contribute to the individual risk of disease. Sequencing can be an effective approach to identify candidate genes and pathways for nsCPO.

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Deletion of the T-box transcription factor gene, Tbx1, in mice induces differential expression of genes associated with cleft palate in humans

Cited by 5 publications

References 35 publications

Craniofacial Phenotypes and Genetics of DiGeorge Syndrome

Craniofacial Phenotypes and Genetics of DiGeorge Syndrome

Current Understanding of Host Genetics of Otitis Media

Ultra-Rare Variants Identify Biological Pathways and Candidate Genes in the Pathobiology of Non-Syndromic Cleft Palate Only

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