Loss of β2-spectrin prevents cardiomyocyte differentiation and heart development.
OBJECTIVE
β2-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.


RESULTS
Disruption 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 α-smooth muscle actin (α-SMA). Furthermore, cytoskeletal networks of dystrophin, F-actin, and α-SMA in cardiomyocytes were disorganized upon loss of β2-spectrin. In addition, deletion of β2-spectrin in mice (Spnb2(tm1a/tm1a)) prevented proper development of the heart in association with disintegration of dystrophin structure and markedly reduced survival.


CONCLUSIONS
These 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.
Radiation Medicine Branch, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, Goyang 410-769, Korea.
Jeong A
JA
Lim
Hye Jung
HJ
Baek
Moon Sun
MS
Jang
Eun Kyoung
EK
Choi
Yong Min
YM
Lee
Sang Jin
SJ
Lee
Sung Chul
SC
Lim
Joo Young
JY
Kim
Tae Hyun
TH
Kim
Hye Sun
HS
Kim
Lopa
L
Mishra
Sang Soo
SS
Kim
D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000502:physiology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000378:metabolism; D016189:Dystrophin / Q000378:metabolism; D005260:Female; D006321:Heart / Q000196:embryology*; D006330:Heart Defects, Congenital / Q000209:etiology*; D008297:Male; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology*; D009210:Myofibrils / Q000378:metabolism; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D013049:Spectrin
D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D016189:Dystrophin; D008840:Microfilament Proteins; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D013049:Spectrin
Cardiogenesis; Cytoskeleton; TGF-β; β2-Spectrin