Hematopoietic-specific Stat5-null mice display microcytic hypochromic anemia associated with reduced transferrin receptor gene expression.
Iron is essential for all cells but is toxic in excess, so iron absorption and distribution are tightly regulated. Serum iron is bound to transferrin and enters erythroid cells primarily via receptor-mediated endocytosis of the transferrin receptor (Tfr1). Tfr1 is essential for developing erythrocytes and reduced Tfr1 expression is associated with anemia. The transcription factors STAT5A/B are activated by many cytokines, including erythropoietin. Stat5a/b(-/-) mice are severely anemic and die perinatally, but no link has been made to iron homeostasis. To study the function of STAT5A/B in vivo, we deleted the floxed Stat5a/b locus in hematopoietic cells with a Tie2-Cre transgene. These mice exhibited microcytic, hypochromic anemia, as did lethally irradiated mice that received a transplant of Stat5a/b(-/-) fetal liver cells. Flow cytometry and RNA analyses of erythroid cells from mutant mice revealed a 50% reduction in Tfr1 mRNA and protein. We detected STAT5A/B binding sites in the first intron of the Tfr1 gene and found that expression of constitutively active STAT5A in an erythroid cell line increased Tfr1 levels. Chromatin immunoprecipitation experiments confirmed the binding of STAT5A/B to these sites. We conclude that STAT5A/B is an important regulator of iron update in erythroid progenitor cells via its control of Tfr1 transcription.
Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDKD), National Institutes of Health (NIH), Bethesda, MD 20892, USA. bingmei@mail.nih.gov
Bing-Mei
BM
Zhu
Sara K
SK
McLaughlin
Risu
R
Na
Jie
J
Liu
Yongzhi
Y
Cui
Cyril
C
Martin
Akiko
A
Kimura
Gertraud W
GW
Robinson
Nancy C
NC
Andrews
Lothar
L
Hennighausen
D000747:Anemia, Hypochromic / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D015672:Erythroid Precursor Cells / Q000378:metabolism; D016332:Fetal Tissue Transplantation; D015870:Gene Expression; D006410:Hematopoiesis / Q000235:genetics / Q000502:physiology; D022781:Hepatocytes / Q000637:transplantation; D007438:Introns; D007501:Iron / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011990:Receptors, Transferrin / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
D017931:DNA Primers; D012333:RNA, Messenger; D011990:Receptors, Transferrin; D050799:STAT5 Transcription Factor; C494093:Stat5a protein, mouse; C494096:Stat5b protein, mouse; C480029:Tfrc protein, mouse; D007501:Iron