Abrogation of TGF-beta signalling in TAGLN expressing cells recapitulates Pentalogy of Cantrell in the mouse.
Abrogation of TGF-beta signalling in TAGLN expressing cells recapitulates Pentalogy of Cantrell in the mouse.
复制标题
DOI：
10.1038/s41598-018-21948-z
复制
发表时间：
2018-02-26
影响因子：
4.6
通讯作者：
Cossu G
中科院分区：
文献类型：
--
作者：
Aldeiri B;Roostalu U;Albertini A;Behnsen J;Wong J;Morabito A;Cossu G
Cantrell五联症是一种罕见的多器官先天性畸形，它阻碍腹体壁闭合，导致疝、心内和心包缺损。导致这些严重发育缺陷的潜在细胞和分子变化仍然未知，主要是由于缺乏代表性的动物模型。在这里，我们提供了在表达Transgelin（Tagln）的细胞中条件性消融TGFβRII的小鼠模型的深入表征。我们表明，Tagln是瞬时表达的各种细胞参与胚胎发育和图案的腹侧结构。基因切除这些细胞中的TGFβRII导致腹侧中线闭合缺陷、疝、心脏流出道扩张和异常心脏分隔，为研究导致PC的形态学变化提供了可靠的模型。我们发现膈肌的肌细胞生成不依赖于TGFβ，而膈疝是由成纤维细胞特异性迁移缺陷引起的。在背体壁中，Tagln表达在闭合过程后启动，揭示了腹体壁和背体壁发育之间的显着差异。我们的研究表明，使用微CT扫描获得一个三维高分辨率的胚胎异常的概述，并提供了第一个机制洞察PC的发展。
Pentalogy of Cantrell (PC) is a rare multi-organ congenital anomaly that impedes ventral body wall closure and results in diaphragmatic hernia, intra- and pericardial defects. The underlying cellular and molecular changes that lead to these severe developmental defects have remained unknown largely due to the lack of representative animal models. Here we provide in depth characterization of a mouse model with conditional ablation of TGFβRII in Transgelin (Tagln) expressing cells. We show that Tagln is transiently expressed in a variety of cells that participate in the embryonic development and patterning of ventral structures. Genetic ablation of TGFβRII in these cells leads to ventral midline closure defect, diaphragmatic hernia, dilated cardiac outflow tract and aberrant cardiac septation, providing a reliable model to study the morphological changes leading to PC. We show that myogenisis in the diaphragm is independent of TGFβ and the diaphragmatic hernia arises from fibroblast-specific migration defect. In the dorsal body wall Tagln expression is initiated after the closure process, revealing a remarkable difference between ventral and dorsal body walls development. Our study demonstrates the use of micro-CT scanning to obtain a 3-dimensional high-resolution overview of embryonic anomalies and provides the first mechanistic insight into the development of PC.
登录
查看更多内容
影响因子：
1.5
作者：
Chytil, A;Magnuson, MA;Moses, HL
通讯作者：
Moses, HL
影响因子：
2.7
作者：
Joeng KS;Schumacher CA;Zylstra-Diegel CR;Long F;Williams BO
通讯作者：
Williams BO
影响因子：
30.8
作者：
KAARTINEN, V;VONCKEN, JW;GROFFEN, J
通讯作者：
GROFFEN, J
影响因子：
2.9
作者：
DUBAND, JL;GIMONA, M;SMALL, JV
通讯作者：
SMALL, JV
影响因子：
14.9
作者：
Chen, SY;Kulik, M;Lechleider, RJ
通讯作者：
Lechleider, RJ