Role of SCL/Tal-1, GATA, and Ets transcription factor binding sites for the regulation of Flk-1 expression during murine vascular development

The receptor tyrosine kinase Flk-1 is essential for embryonic blood vessel development and for tumor angiogenesis. To identify upstream transcriptiona l regulators of Flk-1, the gene regulatory elements that mediate endotheliu m-specific expression in mouse embryos were characterized. By mutational an alysis, binding sites for SCL/Tal-1, GATA, and Ets transcription factors lo cated in the Flk-1 enhancer were identified as critical elements for the en dothelium-specific Flk-1 gene expression in transgenic mice. c-Ets1, a tran scription factor that is coexpressed with Flk-1 during embryonic developmen t and tumor angiogenesis, activated the Flk-1 promoter via 2 binding sites. One of these sites was required for Flk-1 promoter function in the embryon ic vasculature. These results provide the first evidence that SCL/Tal-1, GA TA, and Ets transcription factors act up-stream of Flk-1 In a combinatorial fashion to determine embryonic blood vessel formation and are key regulato rs not only of the hematopoietic program, but also of vascular development, (C) 2000 by The American Society of Hematology.