P47Conditional deletion of Scrib gene in the developing myocardium leads to congenital heart defects

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The Scrib gene is a component of the non-canonical Wnt/planar cell polarity (PCP) pathway which has been implicated in cardiogenesis. Mutation of Scrib, in the Circletail mouse mutant, results in cardiomyocyte disorganisation and disrupted cell-cell adhesion in the early heart tube. This is associated with a spectrum of cardiac septation and alignment defects and abnormalities of the ventricular myocardium that resemble certain types of human cardiomyopathy.

Utilising Cre-LoxPtechnology and Scribf/f mice, we generated embryos with the conditional deletion of Scrib in specific cell types within the developing heart, allowing us to determine the cardiac cell type that is critically dependent on Scrib function. Early deletion of Scrib in cardiac progenitors, utilising Nkx2.5Cre mice, confirmed the importance of Scrib at the earliest stages of myocardial formation, resulting in hearts with ventricular septal defects but a well-developed compact myocardium. Later deletion of Scrib in the myocardium, using Mlc2v-Cre, had only a mild affect on the ventricular myocardium.

We investigated how Scrib functions in the developing myocardium. Scrib localises to the adherens junctions of developing cardiomyocytes. Co-immunoprecipitation and immunofluorescence experiments indicated that Scrib forms a protein complex with Rac1 and its exchange factor, β-Pix, in both the H9C2 cardiomyocyte cell line and in hearts isolated from E10.5 embryos. Moreover, Rac1f/f;Nkx2.5Cre mice share a similar phenotype to Scrib1f/f;Nkx2.5Cre. To examine for a possible genetic interaction between Scrib and Rac1 we generated Scribf/ + ;Rac1f/ + ;Nkx2.5Cre mouse embryos. Double heterozygotes developed heart malformations that closely resembled those seen in Rac1f/f;Nkx2.5Cre embryos, confirming a genetic as well as physical interaction between Scrib and Rac1. These findings suggest that Scrib, together with Rac1, plays essential roles in cardiac progenitors, regulating adhesion and allowing the proper organisation of the myocardium that is essential for ventricular sepum integrity.

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