The Role of Gata2 in Hematopoietic and Vascular Development.

Abstract

Transcription factors play demonstrably critical roles in development. The transcription factor Gata2 is required for the proliferation of hematopoietic progenitors and proper urogenital development. Gata2 null mutant mice die at embryonic day 10.5 from a complete failure of primitive and definitive hematopoiesis; hematopoietic-rescued compound mutant animals succumb to hydroureteronephrosis shortly after birth. The Gata2 null mutant background deficiencies were successfully rescued using a 413-kilobase pair (kbp) linked-Bacterial Artificial Transgene (BAC) containing both the 5’ hematopoietic and 3’ urogenital enhancers. Rescued transgenic mice are both viable and fertile, indicating that the endpoints of this linked-BAC define the functional boundaries of the Gata2 locus. A 290-bp endothelial enhancer of Gata2, termed VE (vascular enhancer), was localized within Gata2 intron 4 and characterized in detail, revealing a requirement for an E box binding site for proper expression from this element. To determine whether GATA-2 is required for the differentiation of definitive hemangioblasts, presumptive common progenitors of both the endothelial and hematopoietic lineages, mice carrying the Gata2 VE element driving cre expression (TgVE-Cre) were generated in order to conditionally ablate Gata2 in this precursor cell type. Through lineage tracing studies in TgVE-Cre:Rosa26RlacZ mice, we provide evidence that precursor cells from the mesoderm give rise to at least a subset of definitive, lineage-restricted hematopoietic cells and endothelial cells. Through understanding of the cis regulatory elements and trans-acting factors that govern Gata2 expression and its role in these developmental processes, our comprehension of the functional networks that are employed during embryonic development has been expanded.