Loss of ß2-spectrin prevents cardiomyocyte differentiation and heart development

Lim JA etc
Cardiovascular Research, 2013

ß2-Spectrin is an actin-binding protein that plays an important role in membrane integrity and the transforming growth factor (TGF)-ß signalling pathway as an adaptor for Smads. Loss of ß2-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 ß2-spectrin in embryogenesis, particularly in heart development, has been poorly delineated. Here, we demonstrated that ß2-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 results
Disruption of ß2-spectrin in primary muscle cells not only inhibited TGF-ß/Smad signalling, but also reduced the expression of the cardiomyocyte differentiation markers Nkx2.5, dystrophin, and a-smooth muscle actin (a-SMA). Furthermore, cytoskeletal networks of dystrophin, F-actin, and a-SMA in cardiomyocytes were disorganized upon loss of ß2-spectrin. In addition, deletion of ß2-spectrin in mice (Spnb2tm1a/tm1a) prevented proper development of the heart in association with disintegration of dystrophin structure and markedly reduced survival.
These data suggest that ß2-spectrin deficiency leads to inactivation of TGF-ß/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 ß2-spectrin is required for proper development of the heart and that disruption of ß2-spectrin is a potential underlying cause of congenital heart defects.

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Cardiovascular Research
DOI: 10.1093/cvr/cvt222
National Cancer Center, Goyang, Korea