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Lookup NU author(s): Dr Veronika Boczonadi, Professor Iain KeenanORCiD, Dr Simon RamsbottomORCiD, Charlotte Donald-Wilson, Dr Bill Chaudhry, Professor Deborah HendersonORCiD
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).
Aims: The organization and maturation of ventricular cardiomyocytes from the embryonic to the adult form is crucial for normal cardiac function. We have shown that a polarity protein, Scrib, may be involved in regulating the early stages of this process. Our goal was to establish whether Scrib plays a cell autonomous role in the ventricular myocardium and whether this involves well-known polarity pathways. Methods and Results: Deletion of Scrib in cardiac precursors utilising Scribflox mice together with the Nkx2.5-Cre driver resulted in disruption of the cytoarchitecture of the forming trabeculae and ventricular septal defects. Although the majority of mice lacking Scrib in the myocardium survived to adulthood, they developed marked cardiac fibrosis. Scrib did not physically interact with the planar cell polarity protein (PCP) Vangl2 in early cardiomyocytes, as it does in other tissues, suggesting that the anomalies did not result from disruption of PCP signaling. However, Scrib interacted with Rac1 physically in embryonic cardiomyocytes and genetically to result in ventricular abnormalities, suggesting that this interaction is crucial for the development of the early myocardium. Conclusions: The Scrib-Rac1 interaction plays a crucial role in the organization of developing cardiomyocytes and formation of the ventricular myocardium. Thus, we have identified a novel signaling pathway in the early, functioning, heart muscle. These data also show that the fetus can recover from relatively severe abnormalities in prenatal ventricular development, although cardiac fibrosis can be a long-term consequence.
Author(s): Boczonadi V, Gillespie R, Keenan ID, Ramsbottom SA, Donald-Wilson C, Al Nazer M, Humbert P, Schwarz RJ, Chaudhry B, Henderson DJ
Publication type: Article
Publication status: Published
Journal: Cardiovascular Research
Year: 2014
Volume: 104
Issue: 1
Pages: 103-115
Print publication date: 01/10/2014
Online publication date: 18/08/2014
Acceptance date: 08/08/2014
Date deposited: 03/11/2014
ISSN (print): 0008-6363
ISSN (electronic): 1755-3245
Publisher: Oxford University Press
URL: http://dx.doi.org/10.1093/cvr/cvu193
DOI: 10.1093/cvr/cvu193
PubMed id: 25139745
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