Activated Braf induces esophageal dilation and gastric epithelial hyperplasia in mice
| Autor: | Yoichi Matsubara, Shingo Takahara, Kazuhiko Yanai, Yoko Aoki, Shin Ichi Inoue, Tetsuya Niihori, Takeo Yoshikawa |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Heart Defects
Congenital Male Proto-Oncogene Proteins B-raf 0301 basic medicine Pathology medicine.medical_specialty Transgene Hyperkeratosis Stomach Diseases Mice Transgenic Biology Pathogenesis Mice 03 medical and health sciences 0302 clinical medicine Germline mutation Ectodermal Dysplasia Genetics medicine Animals Esophagus Craniofacial Protein Kinase Inhibitors Molecular Biology Germ-Line Mutation Genetics (clinical) Mice Inbred ICR Facies Skeletal muscle General Medicine MAP Kinase Kinase Kinases medicine.disease Failure to Thrive 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Failure to thrive Esophageal Stenosis Focal Epithelial Hyperplasia Female medicine.symptom |
| Zdroj: | Human Molecular Genetics. 26:4715-4727 |
| ISSN: | 1460-2083 0964-6906 |
| Popis: | Germline mutations in BRAF are a major cause of cardio-facio-cutaneous (CFC) syndrome, which is characterized by heart defects, characteristic craniofacial dysmorphology and dermatologic abnormalities. Patients with CFC syndrome also commonly show gastrointestinal dysfunction, including feeding and swallowing difficulties and gastroesophageal reflux. We have previously found that knock-in mice expressing a Braf Q241R mutation exhibit CFC syndrome-related phenotypes, such as growth retardation, craniofacial dysmorphisms, congenital heart defects and learning deficits. However, it remains unclear whether BrafQ241R/+ mice exhibit gastrointestinal dysfunction. Here, we report that BrafQ241R/+ mice have neonatal feeding difficulties and esophageal dilation. The esophagus tissues from BrafQ241R/+ mice displayed incomplete replacement of smooth muscle with skeletal muscle and decreased contraction. Furthermore, the BrafQ241R/+ mice showed hyperkeratosis and a thickened muscle layer in the forestomach. Treatment with MEK inhibitors ameliorated the growth retardation, esophageal dilation, hyperkeratosis and thickened muscle layer in the forestomach in BrafQ241R/+ mice. The esophageal dilation with aberrant skeletal-smooth muscle boundary in BrafQ241R/+ mice were recovered after treatment with the histone H3K27 demethylase inhibitor GSK-J4. Our results provide clues to elucidate the pathogenesis and possible treatment of gastrointestinal dysfunction and failure to thrive in patients with CFC syndrome. |
| Databáze: | OpenAIRE |
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