Document Detail


Signaling via the Tgf-beta type I receptor Alk5 in heart development.
MedLine Citation:
PMID:  18718461     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Somyoth Sridurongrit; Jonas Larsson; Robert Schwartz; Pilar Ruiz-Lozano; Vesa Kaartinen
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2008-08-07
Journal Detail:
Title:  Developmental biology     Volume:  322     ISSN:  1095-564X     ISO Abbreviation:  Dev. Biol.     Publication Date:  2008 Oct 
Date Detail:
Created Date:  2008-10-16     Completed Date:  2008-11-18     Revised Date:  2014-09-18    
Medline Journal Info:
Nlm Unique ID:  0372762     Medline TA:  Dev Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  208-18     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis
Cell Communication / drug effects,  physiology
Cell Differentiation / drug effects,  physiology
Cell Lineage
Cell Proliferation / drug effects
Cells, Cultured
Coronary Vessels / cytology,  embryology
Endocardial Cushions / cytology,  embryology
Endocardium / cytology,  embryology
Gene Targeting
Heart / embryology*,  physiology
Mesoderm / cytology,  embryology
Mice
Mice, Mutant Strains
Mice, Transgenic
Myocardium / cytology,  metabolism*
Myocytes, Cardiac / metabolism
Organ Culture Techniques
Pericardium / cytology,  drug effects,  embryology
Protein-Serine-Threonine Kinases / genetics,  metabolism*
Receptors, Transforming Growth Factor beta / genetics,  metabolism*
Signal Transduction / genetics,  physiology*
Transforming Growth Factor beta1 / pharmacology,  physiology*
Grant Support
ID/Acronym/Agency:
DE013085/DE/NIDCR NIH HHS; HL074862/HL/NHLBI NIH HHS; R01 DE013085/DE/NIDCR NIH HHS; R01 DE013085-09/DE/NIDCR NIH HHS; R01 HL065484/HL/NHLBI NIH HHS; R01 HL074862/HL/NHLBI NIH HHS; R01 HL074862-05A1/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Receptors, Transforming Growth Factor beta; 0/Transforming Growth Factor beta1; EC 2.7.1.11/TGF-beta type I receptor; EC 2.7.11.1/Protein-Serine-Threonine Kinases
Comments/Corrections

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