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Notch/Delta signaling constrains reengineering of pro-T cells by PU.1

Franco, Christopher B. and Scripture-Adams, Dierdre D. and Proekt, Irina and Taghon, Tom and Weiss, Angela H. and Yui, Mary A. and Adams, Stephanie L. and Diamond, Rochelle A. and Rothenberg, Ellen V. (2006) Notch/Delta signaling constrains reengineering of pro-T cells by PU.1. Proceedings of the National Academy of Sciences of the United States of America, 103 (32). pp. 11993-11998. ISSN 0027-8424. PMCID PMC1567686. https://resolver.caltech.edu/CaltechAUTHORS:FRApnas06

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PDF (Figure 5. Effects of PU.1 overexpression on normal E14.5 fetal thymocytes in OP9-DL1 and OP9-control stromal coculture.) - Supplemental Material
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PDF (Figure 6. Effects of PU.1 on E14.5 DO11.10 TCR transgenic thymocytes in OP9-DL1 culture: inhibition of DP cell generation from stage-matched c-kit+ cells and from transgenic TCR-expressing cells despite cell-surface TCR complex ...) - Supplemental Material
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PDF (Figure 7. Early effects of PU.1 transduction on Bcl2 transgenic fetal thymocytes in suspension culture: rapid developmental perturbations of the CD25+ Thy-1+ pro-T cell subset caused by PU.1 in the absence of Notch/DL1 signaling...) - Supplemental Material
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PDF (Figure 8. Summary of effects of PU.1 on Bcl2 transgenic thymocytes in OP9-DL1 and OP9-control cultures.) - Supplemental Material
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PDF (Figure 9. Characterization of Mac-1+ cells induced by PU.1 expression in immature Bcl2 transgenic thymocytes.) - Supplemental Material
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PDF (Figure 10. Expression of pro-T cell genes in "primitive" Thy-1low, "Pro-T" Thy-1+ CD25+, and "PreT" Thy-1+ CD25- cells from E15.5 Bcl2 transgenic thymus 15-20 h after transduction.) - Supplemental Material
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PDF (Figure 11. Combinatorial effects of PU.1 and Notch/DL1 signaling on Bcl11 and Egr family gene expression in Bcl2 transgenic fetal thymocytes.) - Supplemental Material
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Abstract

PU.1 is essential for early stages of mouse T cell development but antagonizes it if expressed constitutively. Two separable mechanisms are involved: attenuation and diversion. Dysregulated PU.1 expression inhibits pro-T cell survival, proliferation, and passage through β-selection by blocking essential T cell transcription factors, signaling molecules, and Rag gene expression, which expression of a rearranged T cell antigen receptor transgene cannot rescue. However, Bcl2 transgenic cells are protected from this attenuation and may even undergo β-selection, as shown by PU.1 transduction of defined subsets of Bcl2 transgenic fetal thymocytes with differentiation in OP9-DL1 and OP9 control cultures. The outcome of PU.1 expression in these cells depends on Notch/Delta signaling. PU.1 can efficiently divert thymocytes toward a myeloid-like state with multigene regulatory changes, but Notch/Delta signaling vetoes diversion. Gene expression analysis distinguishes sets of critical T lineage regulatory genes with different combinatorial responses to PU.1 and Notch/Delta signals, suggesting particular importance for inhibition of E proteins, Myb, and/or Gfi1 (growth factor independence 1) in diversion. However, Notch signaling only protects against diversion of cells that have undergone T lineage specification after Thy-1 and CD25 up-regulation. The results imply that in T cell precursors, Notch/Delta signaling normally acts to modulate and channel PU.1 transcriptional activities during the stages from T lineage specification until commitment.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1567686/PubMed CentralArticle
ORCID:
AuthorORCID
Yui, Mary A.0000-0002-3136-2181
Rothenberg, Ellen V.0000-0002-3901-347X
Additional Information:© 2006 The National Academy of Sciences of the USA. Edited by Max D. Cooper, University of Alabama, Birmingham, AL, and approved June 19, 2006 (received for review February 11, 2006). Published online on July 31, 2006, 10.1073/pnas.0601188103. We thank Thomas Graf for discussion of unpublished results; J.-C. Zúñiga-Pflücker (University of Toronto, Toronto, Canada) for OP9 cell lines; Eric Davidson for insightful criticism of the manuscript and kind permission to use the ABI7900HT sequence detector; E.-S. David and C. C. Tydell (both at the California Institute of Technology) for PCR primers and help with quantitative PCR; Robert Butler for fine technical support; and Robin Condie, Ruben Bayon, Lorena Del Carmen Sandoval, Natasha Bouey, and Sherwin Chen for excellent care of mice. This work was supported by U.S. Public Health Service Grants R01 CA90233 and R01 CA98925 and by the DNA Sequencer Royalty Fund at California Institute of Technology. C.B.F. and D.D.S.-A. contributed equally to this work. Author contributions: D.D.S.-A., T.T., M.A.Y., and E.V.R. designed research; C.B.F., D.D.S.-A., I.P., T.T., A.H.W., M.A.Y., and S.L.A. performed research; C.B.F., D.D.S.-A., I.P., T.T., S.L.A., R.A.D., and E.V.R. analyzed data; E.V.R. wrote the paper; and A.H.W. provided crucial background studies. Conflict of interest statement: No conflicts declared. This paper was submitted directly (Track II) to the PNAS office. Correction. PNAS, September 19, 2006, 103(38):14255.
Funders:
Funding AgencyGrant Number
NIHR01 CA90233
NIHR01 CA98925
DNA Sequencer Royalty Fund, CaltechUNSPECIFIED
Subject Keywords:gene regulation; hematopoiesis; lineage commitment; T cell development; transcription factors
Issue or Number:32
PubMed Central ID:PMC1567686
Record Number:CaltechAUTHORS:FRApnas06
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:FRApnas06
Alternative URL:http://dx.doi.org/10.1073/pnas.0601188103
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:9903
Collection:CaltechAUTHORS
Deposited By: Archive Administrator
Deposited On:26 Mar 2008
Last Modified:03 Oct 2019 00:04

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