Letter abstract
Nature Cell Biology 11, 951 - 957 (2009)
Published online: 20 July 2009 | doi:10.1038/ncb1906
A regulatory pathway involving Notch1/
-catenin/Isl1 determines cardiac progenitor cell fate.
Chulan Kwon2, Li Qian1,2, Paul Cheng1,2, Vishal Nigam2,2, Joshua Arnold2 & Deepak Srivastava2
Regulation of multipotent cardiac progenitor cell (CPC) expansion and subsequent differentiation into cardiomyocytes, smooth muscle or endothelial cells is a fundamental aspect of basic cardiovascular biology and cardiac regenerative medicine. However, the mechanisms governing these decisions remain unclear. Here, we show that Wnt/
-catenin signalling, which promotes expansion of CPCs1, 2, 3, is negatively regulated by Notch1-mediated control of phosphorylated -catenin accumulation within CPCs, and that Notch1 activity in CPCs is required for their differentiation. Notch1 positively, and -catenin negatively, regulated expression of the cardiac transcription factors, Isl1, Myocd and Smyd1. Surprisingly, disruption of Isl1, normally expressed transiently in CPCs before their differentiation4, resulted in expansion of CPCs in vivo and in an embryonic stem (ES) cell system. Furthermore, Isl1 was required for CPC differentiation into cardiomyocyte and smooth muscle cells, but not endothelial cells. These findings reveal a regulatory network controlling CPC expansion and cell fate that involves unanticipated functions of -catenin, Notch1 and Isl1 that may be leveraged for regenerative approaches involving CPCs.
- These authors contributed equally in this work.
- Gladstone Institute of Cardiovascular Disease and Departments of Pediatrics and Biochemistry & Biophysics, University of California, San Francisco, 1650 Owens Street, San Francisco, CA 94158, USA.
Correspondence to: Chulan Kwon2 e-mail: ckwon@gladstone.ucsf.edu
Correspondence to: Deepak Srivastava2 e-mail: dsrivastava@gladstone.ucsf.edu
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated.
RESEARCH
miR-145 and miR-143 regulate smooth muscle cell fate and plasticityNature Article (06 Aug 2009)
Functional gene screening in embryonic stem cells implicates Wnt antagonism in neural differentiationNature Biotechnology Research (01 Dec 2002)
Epicardial progenitors contribute to the cardiomyocyte lineage in the developing heartNature Letters to Editor (03 Jul 2008)
See all 35 matches for Research
