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Delayed, asynchronous, and reversible T-lineage specification induced by Notch/Delta signaling

Taghon, Tom N. and David, Elizabeth-Sharon and Zúñiga-Pflücker, Juan Carlos and Rothenberg, Ellen V. (2005) Delayed, asynchronous, and reversible T-lineage specification induced by Notch/Delta signaling. Genes and Development, 19 (8). pp. 965-978. ISSN 0890-9369. PMCID PMC1080135. doi:10.1101/gad.1298305.

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Using the OP9-DL1 system to deliver temporally controlled Notch/Delta signaling, we show that pluripotent hematolymphoid progenitors undergo T-lineage specification and B-lineage inhibition in response to Notch signaling in a delayed and asynchronous way. Highly enriched progenitors from fetal liver require ≥3 d to begin B- or T-lineage differentiation. Clonal switch-culture analysis shows that progeny of some single cells can still generate both B- and T-lineage cells, after 1 wk of continuous delivery or deprivation of Notch/Delta signaling. Notch signaling induces T-cell genes and represses B-cell genes, but kinetics of activation of lineage-specific transcription factors are significantly delayed after induction of Notch target genes and can be temporally uncoupled from the Notch response. In the cells that initiate T-cell differentiation and gene expression most slowly in response to Notch/Delta signaling, Notch target genes are induced to the same level as in the cells that respond most rapidly. Early lineage-specific gene expression is also rapidly reversible in switch cultures. Thus, while necessary to induce and sustain T-cell development, Notch/Delta signaling is not sufficient for T-lineage specification and commitment, but instead can be permissive for the maintenance and proliferation of uncommitted progenitors that are omitted in binary-choice models.

Item Type:Article
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URLURL TypeDescription CentralArticle
Rothenberg, Ellen V.0000-0002-3901-347X
Additional Information:© 2005 Cold Spring Harbor Laboratory. The Authors acknowledge that six months after the full-issue publication date, the Article will be distributed under a Creative Commons CC-BY-NC License (Attribution-NonCommercial 4.0 International License, Accepted March 8, 2005. Received January 14, 2005. We thank Michele K. Anderson for primer sequences; Shirley Pease, Bruce Kennedy, and Armando Mayo of the Caltech Transgenic Animal Facility for timed matings; and Rochelle Diamond, Stephanie Adams, and Pat Koen of the Caltech Flow Cytometry/Cell Sorting Facility for fluorescence-activated cell sorting. This work was supported by grants from the NIH (R01 CA98925 and R01 CA90233).
Funding AgencyGrant Number
NIHR01 CA98925
NIHR01 CA90233
Subject Keywords:GATA-3; hematopoietic progenitor cells; lineage commitment; lymphocyte development; Pax-5; transcription factors
Issue or Number:8
PubMed Central ID:PMC1080135
Record Number:CaltechAUTHORS:20170208-131541820
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:74161
Deposited By: Tony Diaz
Deposited On:08 Feb 2017 21:33
Last Modified:11 Nov 2021 05:25

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