Abstract
The vertebrate Kindlins are an evolutionarily conserved family of proteins critical for integrin signalling and cell adhesion. Kindlin-2 (KIND2) is associated with intercalated discs in mice, suggesting a role in cardiac syncytium development; however, deficiency of Kind2 leads to embryonic lethality. Morpholino knock-down of Kind2 in zebrafish has a pleiotropic effect on development that includes the heart. It therefore remains unclear whether cardiomyocyte Kind2 expression is required for cardiomyocyte junction formation and the development of normal cardiac function. To address this question, the expression of Fermitin 1 and Fermitin 2 (Fit1, Fit2), the two Drosophila orthologs of Kind2, was silenced in Drosophila cardiomyocytes. Heart development was assessed in adult flies by immunological methods and videomicroscopy. Silencing both Fit1 and Fit2 led to a severe cardiomyopathy characterised by the failure of cardiomyocytes to develop as a functional syncytium and loss of synchrony between cardiomyocytes. A null allele of Fit1 was generated but this had no impact on the heart. Similarly, the silencing of Fit2 failed to affect heart function. In contrast, the silencing of Fit2 in the cardiomyocytes of Fit1 null flies disrupted syncytium development, leading to severe cardiomyopathy. The data definitively demonstrate a role for Fermitins in the development of a functional cardiac syncytium in Drosophila. The findings also show that the Fermitins can functionally compensate for each other in order to control syncytium development. These findings support the concept that abnormalities in cardiomyocyte KIND2 expression or function may contribute to cardiomyopathies in humans.
Highlights
The mammalian Kindlins are a family of evolutionarily conserved proteins that mediate cell-cell and cell-matrix adhesion by regulating integrin function [1,2,3]
Silencing Fit1 using the RNAi line from the Vienna Drosophila RNAi centre (VDRC [28]) led to loss of the cardiac syncytium and loss of contiguous b-integrin staining between adjacent cardiomyocytes)(Fig. 2, Hand-Gal4; UAS.Fit1VDRC)
The current findings unequivocally demonstrate that cardiomyocytes must express members of the Fermitin/Kindlin family in order to develop as a functional syncytium
Summary
The mammalian Kindlins are a family of evolutionarily conserved proteins that mediate cell-cell and cell-matrix adhesion by regulating integrin function [1,2,3]. Findings from several animal models suggest that the formation of junctions between neighbouring cardiomyocytes (intercalated discs) may require integrins and integrin binding proteins [4,5,6,7,8]. It is important to understand the role of these proteins because mutations and polymorphisms that affect intercalated disc formation may be associated with the development of cardiomyopathies in humans [6,9,10]. The global knock-down of Kind causes cardiac hyperplasia, disrupts intercalated disc formation and significantly reduces cardiac contractility [11]. These findings link Kind with the development of a functional cardiac syncytium; a cardiomyocyte-specific test of this hypothesis is yet to be conducted
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