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

Sridurongrit, Somyoth; Larsson, Jonas LU ; Schwartz, Robert; Ruiz-Lozano, Pilar and Kaartinen, Vesa (2008) In Developmental Biology 322(1). p.208-218
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 epithelia] (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-beta s (Tgf-beta) play an important role in induction of EMT in the avian epi- and endocardium, the function of Tgf-beta s in corresponding mammalian tissues is still poorly understood. In this... (More)
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 epithelia] (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-beta s (Tgf-beta) play an important role in induction of EMT in the avian epi- and endocardium, the function of Tgf-beta s 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 fit 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-inducecl 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 AIk5 is controlling vascular homeostasis during cardiogenesis. To conclude, Tgf-beta signaling via AIk5 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. (c) 2008 Elsevier Inc, All rights reserved. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
endocardium, Tgf-beta signaling, epicardium, heart development
in
Developmental Biology
volume
322
issue
1
pages
208 - 218
publisher
Elsevier
external identifiers
  • wos:000259790000020
  • scopus:52049084102
ISSN
1095-564X
DOI
10.1016/j.ydbio.2008.07.038
language
English
LU publication?
yes
id
3aee09a1-ff11-4dd0-a9d1-773d099846f0 (old id 1285814)
date added to LUP
2009-02-06 08:47:21
date last changed
2017-09-10 03:35:40
@article{3aee09a1-ff11-4dd0-a9d1-773d099846f0,
  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 epithelia] (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-beta s (Tgf-beta) play an important role in induction of EMT in the avian epi- and endocardium, the function of Tgf-beta s 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 fit 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-inducecl 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 AIk5 is controlling vascular homeostasis during cardiogenesis. To conclude, Tgf-beta signaling via AIk5 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. (c) 2008 Elsevier Inc, All rights reserved.},
  author       = {Sridurongrit, Somyoth and Larsson, Jonas and Schwartz, Robert and Ruiz-Lozano, Pilar and Kaartinen, Vesa},
  issn         = {1095-564X},
  keyword      = {endocardium,Tgf-beta signaling,epicardium,heart development},
  language     = {eng},
  number       = {1},
  pages        = {208--218},
  publisher    = {Elsevier},
  series       = {Developmental Biology},
  title        = {Signaling via the Tgf-beta type I receptor Alk5 in heart development},
  url          = {http://dx.doi.org/10.1016/j.ydbio.2008.07.038},
  volume       = {322},
  year         = {2008},
}