Abstract
During embryonic development, multiple signaling pathways control specification, migration, and differentiation of the vascular endothelial cell precursors, angioblasts. No single gene responsible for the commitment of mesenchymal cells to the angioblast cell fate has been identified as yet. Here we report characterization and functional studies of Etsrp, a novel zebrafish ETS domain protein. etsrp embryonic expression is only restricted to vascular endothelial cells and their earliest precursors. Morpholino knockdown of Etsrp protein function resulted in the complete absence of circulation in zebrafish embryos. Angioblasts in etsrp–morpholino-injected embryos (morphants) failed to undergo migration and differentiation and did not coalesce into functional blood vessels. Expression of all vascular endothelial molecular markers tested was severely reduced in etsrp morphants, whereas hematopoietic markers were not affected. Overexpression of etsrp RNA caused multiple cell types to express vascular endothelial markers. etsrp RNA restored expression of vascular markers in cloche mutants, defective in hematopoietic and endothelial cell formation, arguing that etsrp functions downstream of cloche in angioblast formation. etsrp gene function was also required for endothelial marker induction by the vascular endothelial growth factor (vegf) and stem cell leukemia (scl/tal1). These results demonstrate that Etsrp is necessary and sufficient for the initiation of vasculogenesis.
Highlights
Vasculogenesis, or formation of vascular endothelial cells de novo, begins very early after the initiation of gastrulation in a vertebrate embryo
Anterior is to the left except as noted. (A) five-somite stage. etsrp is expressed within lateral mesoderm in two distinct expression domains, in the anterior and posterior parts of an embryo. (B) 15-somite stage, lateral view. (C) dorsal view. (D) transverse section. etsrp is expressed in two bilateral stripes of presumptive angioblasts within the lateral mesoderm in the anterior and the trunk and posterior parts of an embryo
A stripe of etsrp-expressing cells is apparent at the midline and extends through the middle and posterior parts of an embryo. (E) 26 hpf stage. etsrp is expressed in vascular endothelial cells of the axial, head, and intersomitic vessels
Summary
Vasculogenesis, or formation of vascular endothelial cells de novo, begins very early after the initiation of gastrulation in a vertebrate embryo. Vasculogenesis starts with the formation of the blood islands in the yolk sac and angioblast precursors in the head mesenchyme [1]. The first angioblasts arise from the lateral plate mesoderm, migrate to the trunk midline between tenand 15-somite stages in response to hedgehog signaling, and coalesce to form the primary axial vessels of the trunk, the dorsal aorta, and the cardinal vein [2,3,4]. As well as the mammalian yolk sac, there is a close association between the primitive hematopoietic cells and the developing endothelium, suggestive of a common precursor, the hemangioblast [6]. Zebrafish cloche mutants lack most blood and endothelial cells suggesting that the hemangioblast lineage has been affected [7,8]. Recent knockdown analysis has demonstrated its essential function in blood and dorsal aorta formation in zebrafish embryos [13,14]
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