Loss of β2-spectrin prevents cardiomyocyte differentiation and heart development

Abstract

Aimsβ2-Spectrin is an actin-binding protein that plays an important role in membrane integrity and the transforming growth factor (TGF)-β signalling pathway as an adaptor for Smads. Loss of β2-spectrin in mice (Spnb2-/-) results in embryonic lethality with gastrointestinal, liver, neural, and heart abnormalities that are similar to those in Smad2 +/-Smad3+/- mice. However, to date, the role of β2-spectrin in embryogenesis, particularly in heart development, has been poorly delineated. Here, we demonstrated that β2-spectrin is required for the survival and differentiation of cardiomyocytes, and its loss resulted in defects in heart development with failure of ventricular wall thickening.Methods and resultsDisruption of β2-spectrin in primary muscle cells not only inhibited TGF-β/Smad signalling, but also reduced the expression of the cardiomyocyte differentiation markers Nkx2.5, dystrophin, and -smooth muscle actin (-SMA). Furthermore, cytoskeletal networks of dystrophin, F-actin, and -SMA in cardiomyocytes were disorganized upon loss of β2-spectrin. In addition, deletion of β2-spectrin in mice (Spnb2tm1a/tm1a) prevented proper development of the heart in association with disintegration of dystrophin structure and markedly reduced survival.ConclusionThese data suggest that β2-spectrin deficiency leads to inactivation of TGF-β/Smad signalling and contributes to dysregulation of the cell cycle, proliferation, differentiation, and the cytoskeletal network, and it leads to defective heart development. Our data demonstrate that β2-spectrin is required for proper development of the heart and that disruption of β2-spectrin is a potential underlying cause of congenital heart defects. © 2013 The Author.