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Scrib:Rac1 interactions are required for the morphogenesis of the ventricular myocardium

Lookup NU author(s): Dr Veronika Boczonadi, Dr Iain Keenan, Dr Simon Ramsbottom, Charlotte Donald-Wilson, Professor Deborah Henderson

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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).


Abstract

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.


Publication metadata

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

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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