p63 exerts spatio-temporal control of palatal epithelial cell fate to prevent cleft palate
| Autor: | Richardson, Rose, Mitchell, Karen, Hammond, Nigel, Mollo, Maria Rosaria, Kouwenhoven, Evelyn N., Wyatt, Niki, Donaldson, Ian, Zeef, Leo, Burgis, Timothy, Blance, Rognvald, van Heeringen, Simon J., Stunnenberg, Hendrik G, Zhou, Huiqing, Missero, Caterina, Romano, Rose Anne, Sinha, Satrajit, Dixon, Michael, Dixon, Jill |
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| Přispěvatelé: | Richardson, Rose, Mitchell, Karen, Hammond, Nigel L., Mollo, Maria Rosaria, Kouwenhoven, Evelyn N., Wyatt, Niki D., Donaldson, Ian J., Zeef, Leo, Burgis, Tim, Blance, Rognvald, van Heeringen, Simon J., Stunnenberg, Hendrik G., Zhou, Huiqing, Missero, Caterina, Romano, Rose Anne, Sinha, Satrajit, Dixon, Michael J., Dixon, Jill |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Embryology
Cancer Research Microarrays Cleft Lip and Palate Immunostaining Biochemistry Epithelium Cell Fusion Mice Animal Cells Cell Movement Medicine and Health Sciences Morphogenesis Gene Regulatory Networks Genetics (clinical) Staining Gene Regulatory Network Gene Expression Regulation Developmental Cleft Palate Bioassays and Physiological Analysis Trans-Activator Phosphoprotein Keratins Anatomy Cellular Types Research Article Human Signal Transduction Cell Physiology lcsh:QH426-470 Research and Analysis Methods Transforming Growth Factor beta3 Genetic Congenital Disorders Animals Humans Birth Defects Molecular Biology Cell Proliferation Mouth Epithelial Cell Palate Animal Embryos Biology and Life Sciences Proteins Epithelial Cells Cell Biology Phosphoproteins Ecology Evolution Behavior and Systematic Cytoskeletal Proteins Disease Models Animal lcsh:Genetics Biological Tissue Otorhinolaryngology Specimen Preparation and Treatment Mutation Trans-Activators Digestive System Developmental Biology |
| Zdroj: | PLoS Genetics, Vol 13, Iss 6, p e1006828 (2017) PLoS Genetics Richardson, R, Mitchell, K, Hammond, N, Mollo, M R, Kouwenhoven, E N, Wyatt, N, Donaldson, I, Zeef, L, Burgis, T, Blance, R, van Heeringen, S J, Stunnenberg, H G, Zhou, H, Missero, C, Romano, R A, Sinha, S, Dixon, M & Dixon, J 2017, ' p63 exerts spatio-temporal control of palatal epithelial cell fate to prevent cleft palate ', PL o S Genetics, vol. 13, no. 6, e1006828 . https://doi.org/10.1371/journal.pgen.1006828 |
| ISSN: | 1553-7404 1553-7390 |
| Popis: | Cleft palate is a common congenital disorder that affects up to 1 in 2500 live births and results in considerable morbidity to affected individuals and their families. The aetiology of cleft palate is complex with both genetic and environmental factors implicated. Mutations in the transcription factor p63 are one of the major individual causes of cleft palate; however, the gene regulatory networks in which p63 functions remain only partially characterized. Our findings demonstrate that p63 functions as an essential regulatory molecule in the spatio-temporal control of palatal epithelial cell fate to ensure appropriate fusion of the palatal shelves. Initially, p63 induces periderm formation and controls its subsequent maintenance to prevent premature adhesion between adhesion-competent, intra-oral epithelia. Subsequently, TGFβ3-induced down-regulation of p63 in the medial edge epithelia of the palatal shelves is a pre-requisite for palatal fusion by facilitating periderm migration from, and reducing the proliferative potential of, the midline epithelial seam thereby preventing cleft palate. Author summary Cleft palate is a serious congenital condition which affects approximately 1 in every 2500 births. Cleft palate occurs when the palatal shelves fail to grow, adhere or fuse during development. Mutations in the gene encoding the transcription factor p63 result in cleft palate in humans and mice. However, the role of p63 and how it controls the network of genes to regulate palate development is not well understood.In this study, we demonstrate that p63 controls the spatio-temporal regulation of palatal epithelial cell fate to ensure appropriate palatal adhesion: p63 induces the formation of a flattened layer of epithelial (periderm) cells and controls its subsequent maintenance. We also demonstrate that TGFβ3-induced, down-regulation of p63 in the medial edge epithelial cells, through which the palatal shelves adhere and fuse, controls Jag2-induced periderm migration to the oral and nasal epithelial triangles. In addition, p63 plays a central role in maintaining the proliferative potential of the basal layer of the medial edge epithelia. Our study provides significant new insights into the mechanisms that regulate development of the palate by establishing the role of p63 in governing the fate of the midline epithelial cells. |
| Databáze: | OpenAIRE |
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