EKLF and KLF2 have compensatory roles in embryonic beta-globin gene expression and primitive erythropoiesis

Blood. 2007 Nov 1;110(9):3417-25. doi: 10.1182/blood-2006-11-057307. Epub 2007 Aug 3.

Abstract

The Krüppel-like C2/H2 zinc finger transcription factors (KLFs) control development and differentiation. Erythroid Krüppel-like factor (EKLF or KLF1) regulates adult beta-globin gene expression and is necessary for normal definitive erythropoiesis. KLF2 is required for normal embryonic Ey- and betah1-, but not adult betaglobin, gene expression in mice. Both EKLF and KLF2 play roles in primitive erythroid cell development. To investigate potential interactions between these genes, EKLF/KLF2 double-mutant embryos were analyzed. EKLF(-/-)KLF2(-/-) mice appear anemic at embryonic day 10.5 (E10.5) and die before E11.5, whereas single-knockout EKLF(-/-) or KLF2(-/-) embryos are grossly normal at E10.5 and die later than EKLF(-/-)KLF2(-/-) embryos. At E10.5, Ey- and betah1-globin mRNA is greatly reduced in EKLF(-/-)KLF2(-/-), compared with EKLF(-/-) or KLF2(-/-) embryos, consistent with the observed anemia. Light and electron microscopic analyses of E9.5 EKLF(-/-)KLF2(-/-) yolk sacs, and cytospins, indicate that erythroid and endothelial cells are morphologically more abnormal than in either single knockout. EKLF(-/-)KLF2(-/-) erythroid cells are markedly irregularly shaped, suggesting membrane abnormalities. EKLF and KLF2 may have coordinate roles in a common progenitor to erythroid and endothelial cells. The data indicate that EKLF and KLF2 have redundant functions in embryonic beta-like globin gene expression, primitive erythropoiesis, and endothelial development.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Anemia / embryology
  • Anemia / genetics
  • Anemia / pathology
  • Animals
  • Embryo, Mammalian
  • Erythrocytes / pathology
  • Erythropoiesis / genetics*
  • Female
  • Fetal Blood / cytology*
  • Fetal Blood / metabolism
  • Gene Expression Regulation, Developmental
  • Globins / genetics*
  • Globins / metabolism
  • Kruppel-Like Transcription Factors / physiology*
  • Male
  • Mice
  • Mice, Knockout
  • Pregnancy
  • RNA, Messenger / metabolism
  • Yolk Sac / pathology

Substances

  • Klf2 protein, mouse
  • Kruppel-Like Transcription Factors
  • RNA, Messenger
  • erythroid Kruppel-like factor
  • Globins