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Gata2a and Gata2b are regulated by distinct Notch signals and are individually required for the hemogenic potential of endothelium.


Hematopoietic stem cells (HSCs) emerge during vertebrate embryogenesis from hemogenic endothelial subpopulation of arterial endothelium. These cells are integral to the wall of the early dorsal aorta, yet have the remarkable capacity to transition from a functional component of the endothelium to a founder of adult hematopoiesis. Although it is not understood exactly how hemogenic endothelial cells are specified or when, recent studies in zebrafish have suggested that specification may be initiated by Notch signaling during the convergence of posterior lateral plate mesoderm, prior to the initiation of vasculogenesis. In mice, the transcription factor Gata2 is a putative direct Notch target within the hemogenic endothelium, and is required within the endothelium for both vasculogenesis and HSC formation. Due to chromosomal duplication, teleost fish have two orthologues of Gata2: gata2a and gata2b. In the period leading up to HSC emergence, gata2a is expressed panvascularly and is required for vasculogenesis, the establishment of circulation, maintenance of the arterial program and initiation of hematopoiesis. In contrast, gata2b expression initiates during the medial convergence of PLM and is expressed specifically within the hemogenic endothelial subpopulation, where it is required for HSC formation. Timing, location and specificity of gata2b expression are consistent with induction via somite-to-PLM Notch signaling. To determine whether Notch regulation of Gata2 may be conserved in zebrafish, the genetic relationships between Notch signaling, and the gata2a and gata2b paralogues were explored. Although both are required to produce functional hemogenic endothelium, gata2a and gata2b are regulated by distinct Notch signals within the dorsal aorta. Additionally, recent studies in zebrafish have suggested that the transcription factor scl promotes expression of the essential regulator of HSC emergence runx1 downstream of Notch signaling, similarly to Gata2. The epistasis between Gata2a, Gata2b and Scl was therefore examined. scl and gata2b are coexpressed within the hemogenic endothelium and expression of gata2b is Scl-dependent. Although gata2a is required upstream of both scl and gata2b within the hemogenic endothelium, their loss does not fully account for the hematopoietic defect observed in gata2aum27 mutants. Therefore, this work suggests that gata2a makes additional, unresolved contributions to the establishment of functional hemogenic endothelium.

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