Dynamic regulation of Gata factor levels is more important than their identity

Three Gata transcription factors (Gatal, -2, and -3) are essential for hematopolesis. These factors are thought to play distinct roles because they do not functionally replace each other. For instance, Gata2 messenger RNA (mRNA) expression is highly elevated in Gata1-null erythrold cells, yet this does not rescue the defect. Here, we test whether Gata2 and -3 transgenes rescue the erythrold defect of Gata1-null mice, if expressed in the appropriate spatiotemporal pattern. Gatal, -2, and -3 transgenes driven by j3-globin regulatory elements, directing expression to late stages of differentiation, fail to rescue erythropoiesis in Gata1-null mutants. In contrast, when controlled by Gatal regulatory elements, directing expression to the early stages of differentiation, Gata1, -2, and -3 do rescue the Gata1-null phenotype. The dramatic increase of endogenous Gata2 mRNA in Gata1-null progenitors is not reflected in Gata2 protein levels, invoking translational regulation. Our data show that the dynamic spatiotemporal regulation of Gata factor levels is more important than their identity and provide a paradigm for developmental control mechanisms that are hard-wired in cis-regulatory elements.