Early Endocardial Morphogenesis Requires Scl/Tal1

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Abstract
The primitive heart tube is composed of an outer myocardial and an inner endocardial layer that will give rise to the cardiac valves and septa. Specification and differentiation of these two cell layers are among the earliest events in heart development, but the embryonic origins and genetic regulation of early endocardial development remain largely undefined. We have analyzed early endocardial development in the zebrafish using time-lapse confocal microscopy and show that the endocardium seems to originate from a region in the lateral plate mesoderm that will give rise to hematopoietic cells of the primitive myeloid lineage. Endocardial precursors appear to rapidly migrate to the site of heart tube formation, where they arrive prior to the bilateral myocardial primordia. Analysis of a newly discovered zebrafish Scl/Tal1 mutant showed an additional and previously undescribed role of this transcription factor during the development of the endocardium. In Scl/Tal1 mutant embryos, endocardial precursors are specified, but migration is severely defective and endocardial cells aggregate at the ventricular pole of the heart. We further show that the initial fusion of the bilateral myocardial precursor populations occurs independently of the endocardium and tal1 function. Our results suggest early separation of the two components of the primitive heart tube and imply Scl/Tal1 as an indispensable component of the molecular hierarchy that controls endocardium morphogenesis. In its earliest functional form, the embryonic heart of all vertebrates is a simple linear tube consisting of two cell types. An outer muscular cell layer called the myocardium surrounds an inner vascular cell layer called the endocardium that connects the heart to the vascular system. The integration of both cell types is an important step during heart development, but the formation of the endocardial component of the heart tube is poorly understood. Here, we analyze the formation of the endocardium in the zebrafish embryo and show using time-lapse imaging that it is a highly dynamic structure. In addition, we have identified a zebrafish mutant with a specific defect during endocardial development. This defect is caused by a mutation in T cell acute leukemia 1, a gene that—when misexpressed—causes many cases of childhood leukemias. Here, we show an additional role for this gene during heart development. In mutant embryos, both endocardial and myocardial precursors are specified, but integration of both cell types does not occur properly due to a defective migration of the endocardial precursors. Given the many interactions that occur between the endocardium and the myocardium, our results will provide a more comprehensive understanding of heart development.