title: Architecture of a lymphomyeloid developmental switch controlled by PU.1, Notch and Gata3.
abstract: Hematopoiesis is a classic system with which to study developmental potentials and to investigate gene regulatory networks that control choices among alternate lineages. T-cell progenitors seeding the thymus retain several lineage potentials. The transcription factor PU.1 is involved in the decision to become a T cell or a myeloid cell, and the developmental outcome of expressing PU.1 is dependent on exposure to Notch signaling. PU.1-expressing T-cell progenitors without Notch signaling often adopt a myeloid program, whereas those exposed to Notch signals remain in a T-lineage pathway. Here, we show that Notch signaling does not alter PU.1 transcriptional activity by degradation/alteration of PU.1 protein. Instead, Notch signaling protects against the downregulation of T-cell factors so that a T-cell transcriptional network is maintained. Using an early T-cell line, we describe two branches of this network. The first involves inhibition of E-proteins by PU.1 and the resulting inhibition of Notch signaling target genes. Effects of E-protein inhibition can be reversed by exposure to Notch signaling. The second network is dependent on the ability of PU.1 to inhibit important T-cell transcription factor genes such as Myb, Tcf7 and Gata3 in the absence of Notch signaling. We show that maintenance of Gata3 protein levels by Myb and Notch signaling is linked to the ability to retain T-cell identity in response to PU.1.
authors: Division of Biology 156-29, California Institute of Technology, Pasadena, CA 91125, USA.
authors: Marissa Morales
authors: MM
authors: Del Real
authors: Ellen V
authors: EV
authors: Rothenberg
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D019070:Cell Lineage / Q000235:genetics; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D005812:Genes, Switch / Q000502:physiology; D006410:Hematopoiesis / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D023461:Myeloid Progenitor Cells / Q000378:metabolism / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020598:Proto-Oncogene Proteins c-myb / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics; D013601:T-Lymphocytes / Q000378:metabolism / Q000502:physiology; D060168:Thymocytes / Q000378:metabolism / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D050990:GATA3 Transcription Factor; D011518:Proto-Oncogene Proteins; D020598:Proto-Oncogene Proteins c-myb; D051880:Receptors, Notch; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C494748:Gata3 protein, mouse