The erythroid phenotype of EKLF-null mice: defects in hemoglobin metabolism and membrane stability.
Development of red blood cells requires the correct regulation of cellular processes including changes in cell morphology, globin expression and heme synthesis. Transcription factors such as erythroid Kruppel-like factor EKLF (Klf1) play a critical role in erythropoiesis. Mice lacking EKLF die around embryonic day 14 because of defective definitive erythropoiesis, partly caused by a deficit in beta-globin expression. To identify additional target genes, we analyzed the phenotype and gene expression profiles of wild-type and EKLF null primary erythroid progenitors that were differentiated synchronously in vitro. We show that EKLF is dispensable for expansion of erythroid progenitors, but required for the last steps of erythroid differentiation. We identify EKLF-dependent genes involved in hemoglobin metabolism and membrane stability. Strikingly, expression of these genes is also EKLF-dependent in primitive, yolk sac-derived, blood cells. Consistent with lack of upregulation of these genes we find previously undetected morphological abnormalities in EKLF-null primitive cells. Our data provide an explanation for the hitherto unexplained severity of the EKLF null phenotype in erythropoiesis.
Drissen
Roy
R
Erasmus MC, Department of Cell Biology, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands.
von Lindern
Marieke
M
Kolbus
Andrea
A
Driegen
Siska
S
Steinlein
Peter
P
Beug
Hartmut
H
Grosveld
Frank
F
Philipsen
Sjaak
S
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000378:metabolism; D001798:Blood Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism*; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004912:Erythrocytes / Q000166:cytology / Q000502:physiology*; D004920:Erythropoiesis / Q000502:physiology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006454:Hemoglobins / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors; D051379:Mice; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013629:Tamoxifen / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D018931:Antineoplastic Agents, Hormonal; D001798:Blood Proteins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; C489041:Dmtn protein, mouse; D006454:Hemoglobins; D051741:Kruppel-Like Transcription Factors; D018832:Molecular Chaperones; D010750:Phosphoproteins; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; C080774:erythroid Kruppel-like factor; D013629:Tamoxifen