Activated Braf induces esophageal dilation and gastric epithelial hyperplasia in mice
Activated Braf induces esophageal dilation and gastric epithelial hyperplasia in mice
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DOI：
10.1093/hmg/ddx354
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发表时间：
2017-12-01
影响因子：
3.5
通讯作者：
Aoki, Yoko
中科院分区：
文献类型：
--
作者：
Inoue, Shin-Ichi;Takahara, Shingo;Aoki, Yoko
BRAF的胚系突变是心面部皮肤综合征的主要原因，该综合征以心脏缺陷、特征性颅面畸形和皮肤病为特征。患有氟氯化碳综合征的患者还通常表现为胃肠功能障碍，包括进食和吞咽困难以及胃食道反流。我们之前已经发现，表达BRAF Q241R突变的敲入小鼠表现出与氟氯化碳综合征相关的表型，如生长迟缓、颅面畸形、先天性心脏病和学习障碍。然而，目前尚不清楚BRAF(Q241R/+)小鼠是否表现出胃肠功能障碍。在这里，我们报告了BRAF(Q241R/+)小鼠有新生儿喂养困难和食道扩张。BRAF(Q241R/+)小鼠的食道组织表现为不完全的骨骼肌代换，收缩功能减弱。此外，BRAF(Q241R/+)小鼠表现出角化过度和前胃肌层增厚。MEK抑制剂治疗可改善BRAF(Q241R/+)小鼠的生长迟缓、食道扩张、角化过度和前胃肌层增厚。用组蛋白H3K27去甲基酶抑制剂GSK-J4治疗后，BRAF(Q241R/+)小鼠的食道扩张和异常的骨骼-平滑肌边界得到恢复。我们的结果为阐明CFC综合征患者胃肠功能障碍和生长障碍的发病机制和可能的治疗方法提供了线索。
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 Braf(Q241R/+) mice exhibit gastrointestinal dysfunction. Here, we report that Braf(Q241R/+) mice have neonatal feeding difficulties and esophageal dilation. The esophagus tissues from Braf(Q241R/+) mice displayed incomplete replacement of smooth muscle with skeletal muscle and decreased contraction. Furthermore, the Braf(Q241R/+) 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 Braf(Q241R/+) mice. The esophageal dilation with aberrant skeletal-smooth muscle boundary in Braf(Q241R/+) 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.