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Blood, 15 June 2007, Vol. 109, No. 12, pp. 5481-5490.
Prepublished online as a Blood First Edition Paper on February 27, 2007; DOI 10.1182/blood-2006-11-060491.
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RED CELLS
Dynamic regulation of Gata factor levels is more important than their identity
Rita Ferreira1,
Albert Wai1,
Ritsuko Shimizu2,
Nynke Gillemans1,
Robbert Rottier1,
Marieke von Lindern3,
Kinuko Ohneda3,
Frank Grosveld1,
Masayuki Yamamoto2, and
Sjaak Philipsen1
Departments of1 Cell Biology, Erasmus MC, Rotterdam, The Netherlands; and
2 Center for Tsukuba Advanced Research Alliance and Institute of Basic Medical Sciences, University of Tsukuba, Japan; and
Department of3 Hematology, Erasmus MC, Rotterdam, The Netherlands
Three Gata transcription factors (Gata1, -2, and -3) are essential for hematopoiesis. 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 erythroid cells, yet this does not rescue the defect. Here, we test whether Gata2 and -3 transgenes rescue the erythroid defect of Gata1-null mice, if expressed in the appropriate spatiotemporal pattern. Gata1, -2, and -3 transgenes driven by ß-globin regulatory elements, directing expression to late stages of differentiation, fail to rescue erythropoiesis in Gata1-null mutants. In contrast, when controlled by Gata1 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.

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