Foxp1 coordinates cardiomyocyte proliferation through both cell-autonomous and nonautonomous mechanisms

Y Zhang, S Li, L Yuan, Y Tian, J Weidenfeld… - Genes & …, 2010 - genesdev.cshlp.org
Y Zhang, S Li, L Yuan, Y Tian, J Weidenfeld, J Yang, F Liu, AL Chokas, EE Morrisey
Genes & development, 2010genesdev.cshlp.org
Cardiomyocyte proliferation is high in early development and decreases progressively with
gestation, resulting in the lack of a robust cardiomyocyte proliferative response in the adult
heart after injury. Little is understood about how both cell-autonomous and nonautonomous
signals are integrated to regulate the balance of cardiomyocyte proliferation during
development. In this study, we show that a single transcription factor, Foxp1, can control the
balance of cardiomyocyte proliferation during development by targeting different pathways …
Cardiomyocyte proliferation is high in early development and decreases progressively with gestation, resulting in the lack of a robust cardiomyocyte proliferative response in the adult heart after injury. Little is understood about how both cell-autonomous and nonautonomous signals are integrated to regulate the balance of cardiomyocyte proliferation during development. In this study, we show that a single transcription factor, Foxp1, can control the balance of cardiomyocyte proliferation during development by targeting different pathways in the endocardium and myocardium. Endocardial loss of Foxp1 results in decreased Fgf3/Fgf16/Fgf17/Fgf20 expression in the heart, leading to reduced cardiomyocyte proliferation. This loss of myocardial proliferation can be rescued by exogenous Fgf20, and is mediated, in part, by Foxp1 repression of Sox17. In contrast, myocardial-specific loss of Foxp1 results in increased cardiomyocyte proliferation and decreased differentiation, leading to increased myocardial mass and neonatal demise. We show that Nkx2.5 is a direct target of Foxp1 repression, and Nkx2.5 expression is increased in Foxp1-deficient myocardium. Moreover, transgenic overexpression of Nkx2.5 leads to increased cardiomyocyte proliferation and increased ventricular mass, similar to the myocardial-specific loss of Foxp1. These data show that Foxp1 coordinates the balance of cardiomyocyte proliferation and differentiation through cell lineage-specific regulation of Fgf ligand and Nkx2.5 expression.
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