Novel insights into erythroid development revealed through in vitro differentiation of GATA-1 embryonic stem cells.
Mouse embryonic stem (ES) cells lacking the transcription factor GATA-1 do not produce mature red blood cells either in vivo or in vitro. To define the consequences of GATA-1 loss more precisely, we used an in vitro ES cell differentiation assay that permits enumeration of primitive (EryP) and definitive (EryD) erythroid precursors and recovery of pure erythroid colonies. In contrast to normal ES cells, GATA-1- ES cells fail to generate EryP precursors. EryD precursors, however, are normal in number but undergo developmental arrest and death at the proerythroblast stage. Contrary to initial expectations, arrested GATA-1(-)-definitive proerythroblasts express GATA target genes at normal levels. Transcripts of the related factor GATA-2 are remarkably elevated in GATA-1- proerythroblasts. These findings imply substantial interchangeability of GATA factors in vivo and suggest that GATA-1 normally serves to repress GATA-2 during erythropoiesis. The approach used here is a paradigm for the phenotypic analysis of targeted mutations affecting hematopoietic development.
Weiss
M J
MJ
Division of Hematology-Oncology, Children's Hospital, Dana Farber Cancer Institute, Boston, Massachusetts.
Keller
G
G
Orkin
S H
SH
D000818:Animals; D001483:Base Sequence; D016923:Cell Death; D002454:Cell Differentiation; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004900:Erythroblasts / Q000502:physiology*; D015672:Erythroid Precursor Cells / Q000166:cytology* / Q000502:physiology; D050981:Erythroid-Specific DNA-Binding Factors; D004920:Erythropoiesis / Q000502:physiology*; D050982:GATA1 Transcription Factor; D050989:GATA2 Transcription Factor; D050990:GATA3 Transcription Factor; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D005914:Globins / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D051379:Mice; D008969:Molecular Sequence Data; D011518:Proto-Oncogene Proteins / Q000235:genetics; D020598:Proto-Oncogene Proteins c-myb; D012333:RNA, Messenger / Q000032:analysis; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation
D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D050982:GATA1 Transcription Factor; D050989:GATA2 Transcription Factor; D050990:GATA3 Transcription Factor; C494689:Gata1 protein, mouse; C494712:Gata2 protein, mouse; C494748:Gata3 protein, mouse; D011518:Proto-Oncogene Proteins; D020598:Proto-Oncogene Proteins c-myb; D012333:RNA, Messenger; D015534:Trans-Activators; D014157:Transcription Factors; D005914:Globins