Vascular endothelial and endocardial progenitors differentiate as cardiomyocytes in the absence of Etsrp/Etv2 function.
ABSTRACT Previous studies have suggested that embryonic vascular endothelial, endocardial and myocardial lineages originate from multipotential cardiovascular progenitors. However, their existence in vivo has been debated and molecular mechanisms that regulate specification of different cardiovascular lineages are poorly understood. An ETS domain transcription factor Etv2/Etsrp/ER71 has been recently established as a crucial regulator of vascular endothelial differentiation in zebrafish and mouse embryos. In this study, we show that etsrp-expressing vascular endothelial/endocardial progenitors differentiate as cardiomyocytes in the absence of Etsrp function during zebrafish embryonic development. Expression of multiple endocardial specific markers is absent or greatly reduced in Etsrp knockdown or mutant embryos. We show that Etsrp regulates endocardial differentiation by directly inducing endocardial nfatc1 expression. In addition, Etsrp function is required to inhibit myocardial differentiation. In the absence of Etsrp function, etsrp-expressing endothelial and endocardial progenitors initiate myocardial marker hand2 and cmlc2 expression. Furthermore, Foxc1a function and interaction between Foxc1a and Etsrp is required to initiate endocardial development, but is dispensable for the inhibition of myocardial differentiation. These results argue that Etsrp initiates endothelial and endocardial, and inhibits myocardial, differentiation by two distinct mechanisms. Our findings are important for the understanding of genetic pathways that control cardiovascular differentiation during normal vertebrate development and will also greatly contribute to the stem cell research aimed at regenerating heart tissues.
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ABSTRACT: Several genes have been implicated in heart tube formation, yet we know little about underlying cellular mechanisms. We analyzed the cellular architecture of the migrating myocardial precursors, and find that they form coherent epithelia that mature as they move medially. Mutant analyses indicate that the cardia bifida locus natter (nat) is required for the integrity of the myocardial epithelia. We positionally cloned nat and show that it encodes Fibronectin. During myocardial migration, Fibronectin is deposited at the midline between the endoderm and endocardial precursors, and laterally around the myocardial precursors. Further analyses show that Fibronectin deposition at the midline is required for the timely migration of myocardial precursors, but dispensable for the migration process itself. In the complete absence of Fibronectin, adherens junctions between myocardial precursors do not form properly, suggesting that cell-substratum interactions are required for epithelial organization. These data suggest that myocardial migration is dependent on epithelial integrity.Developmental Cell 04/2004; 6(3):371-82. · 14.03 Impact Factor
Article: Development of the endocardium.[show abstract] [hide abstract]
ABSTRACT: The endocardium, the endothelial lining of the heart, plays complex and critical roles in heart development, particularly in the formation of the cardiac valves and septa, the division of the truncus arteriosus into the aortic and pulmonary trunks, the development of Purkinje fibers that form the cardiac conduction system, and the formation of trabecular myocardium. Current data suggest that the endocardium is a regionally specialized endothelium that arises through a process of de novo vasculogenesis from a distinct population of mesodermal cardiogenic precursors in the cardiac crescent. In this article, we review recent developments in the understanding of the embryonic origins of the endocardium. Specifically, we summarize vasculogenesis and specification of endothelial cells from mesodermal precursors, and we review the transcriptional pathways involved in these processes. We discuss the lineage relationships between the endocardium and other endothelial populations and between the endocardium and the myocardium. Finally, we explore unresolved questions about the lineage relationships between the endocardium and the myocardium. One of the central questions involves the timing with which mesodermal cells, which arise in the primitive streak and migrate to the cardiac crescent, become committed to an endocardial fate. Two competing conceptual models of endocardial specification have been proposed. In the first, mesodermal precursor cells in the cardiac crescent are prespecified to become either endocardial or myocardial cells, while in the second, fate plasticity is retained by bipotential cardiogenic cells in the cardiac crescent. We propose a third model that reconciles these two views and suggest future experiments that might resolve this question.Pediatric Cardiology 02/2010; 31(3):391-9. · 1.30 Impact Factor
Article: Endoderm and heart development.[show abstract] [hide abstract]
ABSTRACT: Since the first half of the 20th century, experimental embryologists have noted a relationship between endoderm cells and the development of cardiac tissue from mesoderm. During the past decade, the accumulation of evidence for an obligatory interaction between endoderm and mesoderm during the specification and terminal differentiation of myocardial, and more recently endocardial, cells has markedly accelerated. Moreover, the endoderm-derived molecules that may regulate these processes are being identified. It now appears that endoderm-derived growth factors regulate the formation of both myocardial and endocardial cells during specification, terminal differentiation, and perhaps morphogenesis of cells in the developing embryonic heart.Developmental Dynamics 05/2000; 217(4):327-42. · 2.54 Impact Factor