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Transgenic over‐expression of GATA‐1 mutant lacking N‐finger domain causes hemolytic syndrome in mouse erythroid cells
Author(s) -
Nakano Mayu,
Ohneda Kinuko,
YamamotoMukai Harumi,
Shimizu Ritsuko,
Ohneda Osamu,
Ohmura Sakie,
Suzuki Mikiko,
Tsukamoto Saho,
Yanagawa Toru,
Yoshida Hiroshi,
Takakuwa Yuichi,
Yamamoto Masayuki
Publication year - 2005
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1111/j.1365-2443.2005.00814.x
Subject(s) - biology , erythropoiesis , reticulocytosis , mutant , gata2 , microbiology and biotechnology , gata transcription factor , embryonic stem cell , transcription factor , haematopoiesis , transgene , gata1 , gene , gene expression , genetics , stem cell , medicine , promoter , anemia
Transcription factor GATA‐1 is essential for erythroid cell differentiation. GATA‐binding motifs have been found in the regulatory regions of various erythroid‐specific genes, suggesting that GATA‐1 contributes to gene regulation during the entire process of erythropoiesis. A GATA‐1 germ‐line mutation results in embryonic lethality due to defective primitive erythropoiesis and GATA‐1‐null embryonic stem cells fails to differentiate beyond the proerythroblast stage. Therefore, the precise roles of GATA‐1 in the later stages of erythropoiesis could not be clarified. Under the control of a GATA‐1 gene hematopoietic regulatory domain, a GATA‐1 mutant lacking the N‐finger domain (ΔNF mutant) was over‐expressed in mice. These mice exhibited abnormal morphology in peripheral red blood cells (RBCs), reticulocytosis, splenomegaly, and erythroid hyperplasia, indicating compensated hemolysis. These mice were extremely sensitive to phenylhydrazine (PHZ), an agent that induces hemolysis, and their RBCs were osmotically fragile. Importantly, the hemolytic response to PHZ was partially restored by the simultaneous expression of wild‐type GATA‐1 with the ΔNF mutant, supporting our contention that ΔNF protein competitively inhibits the function of endogenous GATA‐1. These data provide the first in vivo evidence that the NF domain contributes to the gene regulation that is critical for differentiation and survival of mature RBCs in postnatal erythropoiesis.