β-catenin deficiency causes DiGeorge syndrome-like phenotypes through regulation of Tbx1
β-catenin deficiency causes DiGeorge syndrome-like phenotypes through regulation of Tbx1
复制标题
DOI：
10.1242/dev.045534
复制
发表时间：
2010-04-01
期刊：
影响因子：
4.6
通讯作者：
Ornitz, David M.
中科院分区：
文献类型：
--
作者：
Huh, Sung-Ho;Ornitz, David M.
迪乔治综合征（DGS）是一种常见的遗传性疾病，其特征是咽器畸形以及心血管、颅面和腺体发育缺陷。TBX 1是最可能的候选致病基因，位于与大多数DGS病例相关的22q11.2染色体缺失内。在这里，我们表明，典型的Wnt-β-catenin信号负调控Tbx 1的表达和β-catenin（Ctnnb 1）在小鼠间质失活引起的DGS表型谱内的异常，包括大血管畸形，发育不良的肺动脉和主动脉弓动脉，心脏畸形，小颌畸形，胸腺发育不全和甲状旁腺定位错误。在杂合子Fgf 8或Tbx 1遗传背景下，Wnt-β-连环蛋白信号的异位激活导致DGS-like表型的发生率和严重程度增加。此外，减少Fgf 8的基因剂量挽救了由Ctnnb 1缺失引起的咽弓动脉缺损。这些发现将Wnt-β-catenin信号传导确定为Tbx 1-Fgf 8信号传导途径的关键上游调节因子，并表明影响Wnt-β-catenin信号传导的因素可以改变DGS的发病率和严重程度。
DiGeorge syndrome (DGS) is a common genetic disease characterized by pharyngeal apparatus malformations and defects in cardiovascular, craniofacial and glandular development. TBX1 is the most likely candidate disease-causing gene and is located within a 22q11.2 chromosomal deletion that is associated with most cases of DGS. Here, we show that canonical Wnt-beta-catenin signaling negatively regulates Tbx1 expression and that mesenchymal inactivation of beta-catenin (Ctnnb1) in mice caused abnormalities within the DGS phenotypic spectrum, including great vessel malformations, hypoplastic pulmonary and aortic arch arteries, cardiac malformations, micrognathia, thymus hypoplasia and mislocalization of the parathyroid gland. In a heterozygous Fgf8 or Tbx1 genetic background, ectopic activation of Wnt-beta-catenin signaling caused an increased incidence and severity of DGS-like phenotypes. Additionally, reducing the gene dosage of Fgf8 rescued pharyngeal arch artery defects caused by loss of Ctnnb1. These findings identify Wnt-beta-catenin signaling as a crucial upstream regulator of a Tbx1-Fgf8 signaling pathway and suggest that factors that affect Wnt-beta-catenin signaling could modify the incidence and severity of DGS.