Boczonadi Veronika, Gillespie Rachel, Keenan Iain, Ramsbottom Simon A, Donald-Wilson Charlotte, Al Nazer Mariana, Humbert Patrick, Schwarz Robert J, Chaudhry Bill, Henderson Deborah J
Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
Cell Cycle and Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Australia Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Melbourne, Australia Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Melbourne, Australia Department of Pathology, University of Melbourne, Parkville, Melbourne, Australia.
Cardiovasc Res. 2014 Oct 1;104(1):103-15. doi: 10.1093/cvr/cvu193. Epub 2014 Aug 18.
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.
Deletion of Scrib in cardiac precursors utilizing Scrib(flox) 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 (PCP) protein, Vangl2, in early cardiomyocytes as it does in other tissues, suggesting that the anomalies did not result from disruption of PCP signalling. 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.
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 signalling pathway in the early, functioning, heart muscle. These data also show that the foetus can recover from relatively severe abnormalities in prenatal ventricular development, although cardiac fibrosis can be a long-term consequence.
从胚胎期到成年期，心室心肌细胞的组织和成熟对于正常心脏功能至关重要。我们已表明，一种极性蛋白Scrib可能参与调节这一过程的早期阶段。我们的目标是确定Scrib在心室心肌中是否发挥细胞自主作用，以及这是否涉及众所周知的极性途径。
利用Scrib（flox）小鼠与Nkx2.5-Cre驱动基因，使心脏前体细胞中的Scrib缺失，导致形成的小梁细胞结构破坏和室间隔缺损。尽管心肌中缺乏Scrib的大多数小鼠存活至成年，但它们出现了明显的心脏纤维化。与在其他组织中不同，Scrib在早期心肌细胞中并未与平面细胞极性（PCP）蛋白Vangl2发生物理相互作用，这表明这些异常并非由PCP信号通路破坏所致。然而，Scrib在胚胎心肌细胞中与Rac1发生物理相互作用，并通过基因作用导致心室异常，这表明这种相互作用对于早期心肌的发育至关重要。
Scrib-Rac1相互作用在发育中的心肌细胞组织和心室心肌形成中起关键作用。因此，我们在早期有功能的心肌中发现了一条新的信号通路。这些数据还表明，尽管心脏纤维化可能是长期后果，但胎儿能够从产前心室发育中相对严重的异常中恢复。
