Constitutive expression of PU.1 in fetal hematopoietic progenitors blocks T cell development at the pro-T cell stage.
The essential hematopoietic transcription factor PU.1 is expressed in multipotent thymic precursors but downregulated during T lineage commitment. The significance of PU.1 downregulation was tested using retroviral vectors to force hematopoietic precursors to maintain PU.1 expression during differentiation in fetal thymic organ culture. PU.1 reduced thymocyte expansion and blocked development at the pro-T cell stage. PU.1-expressing cells could be rescued by switching to conditions permissive for macrophage development; thus, the inhibition depends on both lineage and developmental stage. An intact DNA binding domain was required for these effects. PU.1 expression can downregulate pre-Talpha, Rag-1, and Rag-2 in a dose-dependent manner, and higher PU.1 levels induce Mac-1 and Id-2. Thus, downregulation of PU.1 is specifically required for progression in the T cell lineage.
Anderson
Michele K
MK
Division of Biology 156-29, California Institute of Technology, Pasadena, CA 91125, USA.
Weiss
Angela H
AH
Hernandez-Hoyos
Gabriela
G
Dionne
Christopher J
CJ
Rothenberg
Ellen V
EV
D000818:Animals; D001665:Binding Sites; D015415:Biomarkers; D002454:Cell Differentiation; D002455:Cell Division; D004247:DNA / Q000378:metabolism; D015536:Down-Regulation; D015870:Gene Expression; D005822:Genetic Vectors; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D008099:Liver / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D008264:Macrophages / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D016513:Mice, SCID; D009924:Organ Culture Techniques; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D015375:Receptors, Interleukin-2; D012190:Retroviridae; D013601:T-Lymphocytes / Q000166:cytology*; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics*; D000099232:Proto-Oncogene Protein Spi-1
D015415:Biomarkers; D004247:DNA; D011518:Proto-Oncogene Proteins; D015375:Receptors, Interleukin-2; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1