RT Journal Article
SR Electronic
T1 Endothelial TGF-β signaling instructs smooth muscle development in the cardiac outflow tract
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.01.30.925412
DO 10.1101/2020.01.30.925412
A1 Giulia L.M. Boezio
A1 Anabela Bensimon-Brito
A1 Janett Piesker
A1 Stefan Guenther
A1 Christian S.M. Helker
A1 Didier Y.R. Stainier
YR 2020
UL http://biorxiv.org/content/early/2020/01/31/2020.01.30.925412.abstract
AB The development of the cardiac outflow tract (OFT), which connects the heart to the great arteries, relies on a complex crosstalk between endothelial (ECs) and smooth muscle (SMCs) cells. Defects in OFT development can lead to severe malformations, including aortic aneurysms, which have often been associated with impaired TGF-β signaling. To further investigate the role of TGF-β signaling in OFT formation, we generated zebrafish lacking the type I TGF-β receptor Alk5 and found a strikingly specific dilation of the OFT. alk5 mutants also exhibit increased EC numbers, extracellular matrix (ECM) and SMC disorganization. Surprisingly, endothelial-specific alk5 overexpression in alk5 mutants rescues both endothelial and SMC defects. Furthermore, modulation of the ECM gene fibulin-5, a TGF-β target, partially restores OFT morphology and function. These findings reveal a new requirement for endothelial TGF-β signaling in OFT morphogenesis and suggest an important role for the endothelium in the etiology of aortic malformations.