Notch/Delta signaling constrains reengineering of pro-T cells by PU.1
Open accessAbstract
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.
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In primary pro-T cells and Scid.adh.2C2 cells, highly overexpressed PU.1 appears to inhibit Notch signaling, as measured by downregulation of Notch target genes and Notch1 itself.
“In primary pro-T cells and Scid.adh.2C2 cells, highly overexpressed PU.1 appears to inhibit Notch signaling, as measured by downregulation of Notch target genes and even Notch1 itself.”
From Mechanisms of Action of Hematopoietic Transcription Factor PU.1 in Initiation of T-Cell Development (2019) · cites this paper as [49]
In “Notch/Delta Signaling as a Specific Modifier of PU.1 Actions on Target” (p. 4), the paper says that Notch1 and Notch signal delivery were unaffected by PU.1 in Thy-1+ pro-T cells, and that two Notch target genes were virtually indifferent to PU.1. It does report PU.1 sensitivity of HES-1 and downregulation of Notch1 in a different, Thy-1-low subset, but those qualifications do not support the claimed inhibition in pro-T cells. The cited passages do not establish the claim for Scid.adh.2C2 cells. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredEven artificially high-level PU.1 can redirect differentiation to myeloid or dendritic fates only if Notch signaling is reduced.
“Even artificially high-level PU.1 could only redirect the differentiation of the cells to myeloid or dendritic fates if Notch signaling were reduced (49, 50, 58).”
From Mechanisms of Action of Hematopoietic Transcription Factor PU.1 in Initiation of T-Cell Development (2019) · cites this paper as [49]
The paper reports that Notch/Delta signaling prevents PU.1-driven myeloid diversion in T-lineage-specified pro-T cells (p. 1; Discussion, p. 5). But the Results (p. 4) show that earlier Thy-1-negative precursors generated myeloid-like cells after PU.1 expression even with Notch/Delta signaling. Thus the claim’s unqualified “only if” does not hold for all the cells studied. (LLM, conf=0.88)
Experimental — accuracy not yet measuredRe-expression of PU.1 after T-cell commitment turns on myeloid genes and can transform later pro-T cells into dendritic cells, macrophages, or promyelocytic-like cells.
“re-expression of PU.1 after T-cell commitment turns on myeloid genes and readily transforms later pro-T cells into dendritic cells, macrophages, or promyelocytic-like cells (46–50).”
From Mechanisms of Action of Hematopoietic Transcription Factor PU.1 in Initiation of T-Cell Development (2019) · cites this paper as [49]
In the Results (p. 4), PU.1-transduced pro-T and pre-T cells activate a broad spectrum of myeloid genes and can acquire myeloid markers. The paper does not establish that later committed cells readily become each of the three named cell types: it describes myeloid-like cells, cites earlier work for a dendritic-cell fate (p. 1), and reports that Notch/Delta signaling blocks diversion in the specified cells (p. 4). (LLM, conf=0.88)
Experimental — accuracy not yet measuredPU.1 actions are Notch-sensitive.
“PU.1 actions are Notch-sensitive.”
From Mechanisms of Action of Hematopoietic Transcription Factor PU.1 in Initiation of T-Cell Development (2019) · cites this paper as [49]
Added PU.1 strongly inhibits proliferation of pro-T cells under conditions that do not reward lineage switching.
“it strongly inhibits the proliferation of pro-T cells under conditions that do not reward the cells for lineage switching (49).”
From Mechanisms of Action of Hematopoietic Transcription Factor PU.1 in Initiation of T-Cell Development (2019) · cites this paper as [49]
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“1 and the Notch signaling pathway (49, 58).”
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- Authors
- Franco, C. B., Scripture-Adams, D. D., Proekt, I., Taghon, T., Weiss, A. H., Yui, M. A., Adams, S. L., Diamond, R. A., & Rothenberg, E. V.
- Affiliations
- California Institute of Technology (US)
- University of Southern California (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2006-08-08
- Volume
- 103
- Issue
- 32
- Pages
- 11993-11998
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1567686
- OpenAlex
- W2149251213
- Cited by
- 109
- References
- 34
- Citations by year
- 2026: 1 · 2024: 4 · 2023: 2 · 2022: 1 · 2021: 4 · 2020: 5 · 2019: 8 · 2018: 5 · 2017: 3 · 2016: 7 · 2015: 5 · 2014: 3 · 2013: 11 · 2012: 4
- FWCI
- 3.04
- Type
- journal article
- Language
- en
- Update notices
- correction (2006-09-19)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Funders
- California Institute of Technology
- University of Toronto
- U.S. Public Health Service
- National Cancer Institute (R01CA98925, R01CA90233, R01CA090233, R01CA098925)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- PU.1, Delta-Notch signaling, T cell development, pro-T cells, beta-selection, Bcl-2, E protein, MYB, GFI1, transcriptional regulation, thymocytes, RAG genes, T cell receptor
- MeSH terms
- Proto-Oncogene Protein Spi-1, Animals, Cell Survival, Gene Expression Regulation, Mice, Inbred C57BL, Mice, Transgenic, Models, Biological, Proto-Oncogene Proteins, T-Lymphocytes, Receptors, Interleukin-2, Signal Transduction, Trans-Activators, Cell Lineage, Proto-Oncogene Proteins c-bcl-2, Mice, Receptor, Notch1
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