Mice conditionally expressing RET(C618F) mutation display C cell hyperplasia and hyperganglionosis of the enteric nervous system
Mice conditionally expressing RET(C618F) mutation display C cell hyperplasia and hyperganglionosis of the enteric nervous system
复制标题
条件性表达 RET(C618F) 突变的小鼠表现出 C 细胞增生和肠神经系统神经节增多症
作者：
Okamoto M;Yoshioka Y;Maeda K;Bito Y;Fukumoto T;Uesaka T;Enomoto H
甲状腺髓样癌（MTC）由甲状腺 C 细胞增生发展而来，是甲状腺癌死亡的主要原因之一。 RET 基因富含半胱氨酸结构域 (CRD) 的突变是 MTC 最常见的遗传原因。目前的共识认为，此类半胱氨酸突变会导致配体独立的二聚化和 RET 的组成型激活。然而，鉴于 CRD 突变的数量尚未确定，我们对 CRD 突变导致 MTC 的发病机制的理解仍然不完整。我们在此报告，RET（C618F）是在 MTC 患者中发现的一种突变，表现出中等高的基础活性，需要配体才能完全激活。为了评估RET(C618F)在器官发生中的生物学意义，我们构建了通过Ret启动子条件表达RET(C618F)cDNA的敲入小鼠系。通过 Cre-loxP 重组，可以将 RET(C618F) 等位基因变成 Ret 无效并表达 mCherry，从而可以评估 RET(C618F) 在体内的生物学影响。表达 RET(C618F) 的小鼠表现出轻度 C 细胞增生和肠神经元数量增加，表明 RET(C618F) 赋予功能获得表型。该小鼠品系可作为研究 MTC 和肠神经节过度症发病机制的新型生物平台。
Medullary thyroid carcinoma (MTC) develops from hyperplasia of thyroid C cells and represents one of the major causes of thyroid cancer mortality. Mutations in the cysteine‐rich domain (CRD) of theRETgene are the most prevalent genetic cause of MTC. The current consensus holds that such cysteine mutations cause ligand‐independent dimerization and constitutive activation of RET. However, given the number of the CRD mutations left uncharacterized, our understanding of the pathogenetic mechanisms by which CRD mutations lead to MTC remains incomplete. We report here that RET(C618F), a mutation identified in MTC patients, displays moderately high basal activity and requires the ligand for its full activation. To assess the biological significance ofRET(C618F)in organogenesis, we generated a knock‐in mouse line conditionally expressingRET(C618F)cDNA by theRetpromoter. TheRET(C618F)allele can be made to be Ret‐null and express mCherry by Cre‐loxP recombination, which allows the assessment of the biological influence of RET(C618F) in vivo. Mice expressing RET(C618F) display mild C cell hyperplasia and increased numbers of enteric neurons, indicating that RET(C618F) confers gain‐of‐function phenotypes. This mouse line serves as a novel biological platform for investigating pathogenetic mechanisms involved in MTC and enteric hyperganglionosis.