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The phenotype of mice carrying the  Gata1low    mutation that decreases expression of  Gata1  in erythroid cells and megakaryocytes, includes anemia, thrombocytopenia, hematopoietic failure in bone marrow and development of extramedullary hematopoiesis in spleen. With age, these mice develop myelofibrosis, a disease sustained by alterations in stem/progenitor cells and megakaryocytes. This study analyzed the capacity of  hGATA1  driven by a  μLCR / β-globin  promoter to rescue the phenotype induced by the  Gata1low    mutation in mice. Double  hGATA1 / Gata1low/0    mice were viable at birth with hematocrits greater than those of their  Gata1low/0    littermates but platelet counts remained lower than normal.  hGATA1  mRNA was expressed by progenitor and erythroid cells from double mutant mice but not by megakaryocytes analyzed in parallel. The erythroid cells from  hGATA1/Gata1low/0    mice expressed greater levels of GATA1 protein and of  α - and  β -globin mRNA than cells from  Gata1low/0    littermates and a reduced number of them was in apoptosis. By contrast,  hGATA1/Gata1low/0    megakaryocytes expressed barely detectable levels of GATA1 and their expression of acetylcholinesterase, Von Willebrand factor and platelet factor 4 as well as their morphology remained altered. In comparison with  Gata1+/0    littermates,  Gata1low/0    mice contained significantly lower total and progenitor cell numbers in bone marrow while the number of these cells in spleen was greater than normal. The presence of  hGATA1  greatly increased the total cell number in the bone marrow of  Gata1low/0    mice and, although did not affect the total cell number of the spleen which remained greater than normal, it reduced the frequency of progenitor cells in this organ. The ability of  hGATA1  to rescue the hematopoietic functions of the bone marrow of the double mutants was confirmed by the observation that these mice survive well splenectomy and did not develop myelofibrosis with age. These results indicate that  hGATA1  under the control of  µLCR/β-globin  promoter is expressed in adult progenitors and erythroid cells but not in megakaryocytes rescuing the erythroid but not the megakaryocyte defect induced by the  Gata1low/0    mutation.

frontiers in genetics

hGATA1 Under the Control of a μLCR/β-Globin Promoter Rescues the Erythroid but Not the Megakaryocytic Phenotype Induced by the Gata1low Mutation in Mice