Article

Signaling via the Tgf-beta type I receptor Alk5 in heart development.

University of Michigan, Department of Biologic and Materials Sciences, Ann Arbor, MI 48109, USA.
Developmental Biology (impact factor: 4.07). 09/2008; 322(1):208-18. DOI:10.1016/j.ydbio.2008.07.038
Source: PubMed

ABSTRACT Trophic factors secreted both from the endocardium and epicardium regulate appropriate growth of the myocardium during cardiac development. Epicardially-derived cells play also a key role in development of the coronary vasculature. This process involves transformation of epithelial (epicardial) cells to mesenchymal cells (EMT). Similarly, a subset of endocardial cells undergoes EMT to form the mesenchyme of endocardial cushions, which function as primordia for developing valves and septa. While it has been suggested that transforming growth factor-betas (Tgf-beta) play an important role in induction of EMT in the avian epi- and endocardium, the function of Tgf-betas in corresponding mammalian tissues is still poorly understood. In this study, we have ablated the Tgf-beta type I receptor Alk5 in endo-, myo- and epicardial lineages using the Tie2-Cre, Nkx2.5-Cre, and Gata5-Cre driver lines, respectively. We show that while Alk5-mediated signaling does not play a major role in the myocardium during mouse cardiac development, it is critically important in the endocardium for induction of EMT both in vitro and in vivo. Moreover, loss of epicardial Alk5-mediated signaling leads to disruption of cell-cell interactions between the epicardium and myocardium resulting in a thinned myocardium. Furthermore, epicardial cells lacking Alk5 fail to undergo Tgf-beta-induced EMT in vitro. Late term mutant embryos lacking epicardial Alk5 display defective formation of a smooth muscle cell layer around coronary arteries, and aberrant formation of capillary vessels in the myocardium suggesting that Alk5 is controlling vascular homeostasis during cardiogenesis. To conclude, Tgf-beta signaling via Alk5 is not required in myocardial cells during mammalian cardiac development, but plays an irreplaceable cell-autonomous role regulating cellular communication, differentiation and proliferation in endocardial and epicardial cells.

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Keywords

avian epi-
 
cell-cell interactions
 
corresponding mammalian tissues
 
endocardial cells undergoes EMT
 
epicardial Alk5-mediated signaling
 
epicardial cells
 
epicardial lineages
 
Epicardially-derived cells
 
Gata5-Cre driver lines
 
mammalian cardiac development
 
mesenchymal cells
 
mouse cardiac development
 
myocardial cells
 
smooth muscle cell layer
 
term mutant embryos
 
Tgf-beta type
 
thinned myocardium
 
transforming growth factor-betas
 
Trophic factors secreted
 
vascular homeostasis
 

Vesa Kaartinen