Fetal expression of a human Agamma globin transgene rescues globin chain imbalance but not hemolysis in EKLF null mouse embryos.
Mice lacking the erythroid Kruppel-like factor (EKLF) die in utero at embryonic day 15 (E15) from severe anemia. EKLF(-/-) embryos display a marked deficit in beta-globin gene expression. To test whether beta-globin deficiency was solely responsible for the anemia and intrauterine death, we corrected the globin chain imbalance in EKLF(-/-) embryos by breeding with a strain of mice that express high levels of human gamma-globin. Despite efficient production of hybrid malpha(2)-hgamma(2) hemoglobin in the fetal livers of EKLF(-/-) animals, hemolysis was not corrected and survival was not prolonged. We concluded that deficiency of nonglobin EKLF target genes is a major contributor to the definitive red blood cell abnormalities and prenatal death in EKLF(-/-) embryos. These results suggest that strategies designed to antagonize EKLF function in adults with hemoglobinopathy, in an attempt to reactivate gamma-globin gene expression, may adversely affect other essential aspects of red blood cell physiology. (Blood. 2000;95:1827-1833)
Perkins
A C
AC
Children's Hospital and the Howard Hughes Medical Research Institute, and Harvard Medical School, Boston, MA 02115, USA.
Peterson
K R
KR
Stamatoyannopoulos
G
G
Witkowska
H E
HE
Orkin
S H
SH
D000740:Anemia / Q000235:genetics; D000818:Animals; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005313:Fetal Death / Q000235:genetics; D005804:Genes, Lethal; D005816:Genetic Complementation Test; D005914:Globins / Q000096:biosynthesis* / Q000235:genetics; D006454:Hemoglobins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D006461:Hemolysis / Q000235:genetics*; D006801:Humans; D051741:Kruppel-Like Transcription Factors; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D055503:Protein Multimerization; D013045:Species Specificity; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D019076:Transgenes
D004268:DNA-Binding Proteins; D006454:Hemoglobins; D051741:Kruppel-Like Transcription Factors; D014157:Transcription Factors; C080774:erythroid Kruppel-like factor; D005914:Globins