Abrogation of TGF-beta signalling in TAGLN expressing cells recapitulates Pentalogy of Cantrell in the mouse.

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.

坎特雷尔五联症（PC）是一种罕见的多器官先天性异常，它阻碍腹侧壁闭合，并导致膈疝、心内和心包缺损。由于缺乏具有代表性的动物模型，导致这些严重发育缺陷的潜在细胞和分子变化在很大程度上仍然未知。在此，我们对在表达转胶蛋白（Tagln）的细胞中条件性敲除转化生长因子β受体II（TGFβRII）的小鼠模型进行了深入的特征描述。我们发现，Tagln在多种参与胚胎发育和腹侧结构模式形成的细胞中短暂表达。在这些细胞中对TGFβRII进行基因敲除会导致腹中线闭合缺陷、膈疝、心脏流出道扩张以及心脏间隔异常，为研究导致PC的形态学变化提供了一个可靠的模型。我们发现，膈肌中的肌发生与TGFβ无关，膈疝是由成纤维细胞特异性迁移缺陷引起的。在背侧壁，Tagln的表达在闭合过程之后才开始，这揭示了腹侧壁和背侧壁发育之间的显著差异。我们的研究展示了利用微计算机断层扫描（micro - CT）来获取胚胎异常的三维高分辨率全貌，并首次对PC的发育提供了机制上的见解。