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

Bashar Aldeiri,Julia Behnsen,Alessandra Albertini,Jason Wong,Antonino Morabito,Giulio Cossu,Urmas Roostalu

doi:10.1038/s41598-018-21948-z

Abstract

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.

Highlights

Pentalogy of Cantrell (PC) is a rare congenital anomaly with an estimated incidence of 1 in 200,000 live births[1]
We are reporting an anterior diaphragmatic hernia in this model making the congenital defects in the Tagln-Cre:Tgfbr2flx/flx mouse model of highly representation of the PC anomaly seen in humans
We provide here a comprehensive description of a mouse model for Pentalogy of Cantrell

Summary

Introduction

Pentalogy of Cantrell (PC) is a rare congenital anomaly with an estimated incidence of 1 in 200,000 live births[1]. Cantrell and colleagues suggested that the varied congenital anomalies seen in the pentad are all of mesodermal origin and possibly take place within the first 18 days of embryonic development[5] They postulated that failure in the development in a segment of the lateral plate mesoderm leads to defective septum transversum, pericardial and intra-cardiac defects. In the developing embryo transforming growth factor β (TGFβ) signalling plays a pivotal role in facilitating closure of the embryonic midline[11] It is essential for cell homeostasis in general and is crucial for cardiac and vascular development[12,13]. TGFβ signalling inactivation in Tagln expressing cells leads to ventral body wall closure defect, cardiac and great vessels anomalies[15,17,29]. We are reporting an anterior diaphragmatic hernia in this model making the congenital defects in the Tagln-Cre:Tgfbr2flx/flx mouse model of highly representation of the PC anomaly seen in humans

Methods

Results

Conclusion