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Architecture of a lymphomyeloid developmental switch controlled by PU.1, Notch and Gata3

Del Real, Marissa Morales and Rothenberg, Ellen V. (2013) Architecture of a lymphomyeloid developmental switch controlled by PU.1, Notch and Gata3. Development, 140 (6). pp. 1207-1219. ISSN 0950-1991. PMCID PMC3585658. doi:10.1242/dev.088559. https://resolver.caltech.edu/CaltechAUTHORS:20130328-110147486

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1242/dev.088559DOIArticle
http://dev.biologists.org/content/140/6/1207PublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3585658/PubMed CentralArticle
ORCID:
AuthorORCID
Rothenberg, Ellen V.0000-0002-3901-347X
Additional Information:© 2013 Published by The Company of Biologists Ltd. Accepted 21 December 2012. We thank Avinash Bhandoola, Warren Pear and Gabriela Hernandez-Hoyos for constructs; the entire Rothenberg lab for help and valuable discussions; Robert Butler for technical expertise; Va Si for pilot Gata3 staining experiments; Rochelle Diamond, Diana Perez and Josh Verceles for cell sorting; and Scott Washburn for mouse care. Funding: The work was supported by the National Institutes of Health (NIH) [CA90233 and CA90233-08S1], by the Garfinkle Memorial Laboratory Fund, by the Al Sherman Foundation, by a NIH predoctoral training grant [T32GM07616 to M.M.D.R.] and by the Albert Billings Ruddock Biology Professorship (E.V.R.). Deposited in PMC for release after 12 months.
Funders:
Funding AgencyGrant Number
NIHCA90233
NIHCA90233-08S1
Louis A. Garfinkle Memorial Laboratory FundUNSPECIFIED
Al Sherman FoundationUNSPECIFIED
NIH Predoctoral FellowshipT32GM07616
Albert Billings Ruddock Biology ProfessorshipUNSPECIFIED
Subject Keywords:Gene regulatory network, Lineage decision, Myb, Quantitative gene expression analysis, T-cell development, Sfpi1, Mouse
Issue or Number:6
PubMed Central ID:PMC3585658
DOI:10.1242/dev.088559
Record Number:CaltechAUTHORS:20130328-110147486
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20130328-110147486
Official Citation:Marissa Morales Del Real and Ellen V. Rothenberg Architecture of a lymphomyeloid developmental switch controlled by PU.1, Notch and Gata3 Development 2013 140:1207-1219; doi:10.1242/dev.088559
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:37674
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:11 Apr 2013 18:45
Last Modified:09 Nov 2021 23:30

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