Biomedical subjects

Ellen V Rothenberg

Publications and source records attributed to Ellen V Rothenberg.

7 recordsLinked to original sources

PubMed2003

Regulatory coding of lymphoid lineage choice by hematopoietic transcription factors.

During lymphopoiesis, precursor cells negotiate a complex regulatory space, defined by the levels of several competing and cross-regulating transcription factors, before arriving at stable states of commitment to the B-, T- and NK-specific developmental programs. Recent perturbation experiments provide evidence that this space has three major axes, corresponding to the PU.1 versus GATA-1 balance, the intensity of Notch signaling through the CSL pathway, and the ratio of E-box transcription factors to their Id protein antagonists.

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PubMed2003

GATA-3 expression is controlled by TCR signals and regulates CD4/CD8 differentiation.

GATA-3 is expressed at higher levels in CD4 than in CD8 SP thymocytes. Here we show that upregulation of GATA-3 expression in DP thymocytes is triggered by TCR stimulation, and the extent of upregulation correlates with the strength of the TCR signal. Overexpression of GATA-3 or a partial GATA-3 agonist during positive selection inhibits CD8 SP cell development but is not sufficient to divert class I-restricted T cell precursors to the CD4 lineage. Conversely, expression of the GATA-3 antagonist ROG or of a GATA-3 siRNA hairpin markedly enhances development of CD8 SP cells and reduces CD4 SP development. We propose that GATA-3 contributes to linking the TCR signal strength to the differentiation program of CD4 and CD8 thymocytes.

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PubMed2002

Elements of transcription factor network design for T-lineage specification.

The complex spectrum of cell types produced in mammalian hematopoiesis can be understood as the output of highly combinatorial transcription factor action. The generation of multiple diverse combinations of transcription factors from the common starting state of the hematopoietic stem cell must be explained through the cross-regulatory interactions of these transcription factors at several levels. Here, the operation of such a network is addressed through a focus on murine T cell development, where we have recently established regulatory linkages between GATA-3 and PU.1 and multiple other factors essential to this differentiation pathway. The action of both essential/rate-limiting factors and factors with effects that shift qualitatively with dose and time of action can be traced through the regulatory interaction network. Hypothetical models are proposed to indicate the network nodes that are differentially activated in normal T cell lineage progression and in cells diverted to other potential fates.

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PubMed2002

Definition of regulatory network elements for T cell development by perturbation analysis with PU.1 and GATA-3.

PU.1 and GATA-3 are transcription factors that are required for development of T cell progenitors from the earliest stages. Neither one is a simple positive regulator for T lineage specification, however. When expressed at elevated levels at early stages of T cell development, each of these transcription factors blocks T cell development within a different, characteristic time window, with GATA-3 overexpression initially inhibiting at an earlier stage than PU.1. These perturbations are each associated with a distinct spectrum of changes in the regulation of genes needed for T cell development. Both transcription factors can interfere with expression of the Rag-1 and Rag-2 recombinases, while GATA-3 notably blocks PU.1 and IL-7Ralpha expression, and PU.1 reduces expression of HES-1 and c-Myb. A first-draft assembly of the regulatory targets of these two factors is presented as a provisional gene network. The target genes identified here provide insight into the basis of the effects of GATA-3 or PU.1 overexpression and into the regulatory changes that distinguish the developmental time windows for these effects.

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PubMed2002

T-lineage specification and commitment: a gene regulation perspective.

T lymphocytes originate from pluripotent precursors and undergo lasting commitment to the T cell developmental fate during their processing in the thymus. Commitment includes both the acquisition of essential T cell characteristics and the foreclosing of other developmental options. Gain of T cell characteristics is probably mediated by separate mechanisms, at least in detail, from loss of alternative developmental potentials. Programmed shifts in survival requirements make changes irreversible. Here we review the current evidence identifying the regulatory components of this commitment pathway, and the first hints of how they work together. Roles for PU.1, GATA-3, and their target genes are highlighted.

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PubMed2002

Constitutive expression of PU.1 in fetal hematopoietic progenitors blocks T cell development at the pro-T cell stage.

The essential hematopoietic transcription factor PU.1 is expressed in multipotent thymic precursors but downregulated during T lineage commitment. The significance of PU.1 downregulation was tested using retroviral vectors to force hematopoietic precursors to maintain PU.1 expression during differentiation in fetal thymic organ culture. PU.1 reduced thymocyte expansion and blocked development at the pro-T cell stage. PU.1-expressing cells could be rescued by switching to conditions permissive for macrophage development; thus, the inhibition depends on both lineage and developmental stage. An intact DNA binding domain was required for these effects. PU.1 expression can downregulate pre-Talpha, Rag-1, and Rag-2 in a dose-dependent manner, and higher PU.1 levels induce Mac-1 and Id-2. Thus, downregulation of PU.1 is specifically required for progression in the T cell lineage.

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PubMed2002

Lineage plasticity and commitment in T-cell development.

The earliest stages of intrathymic T-cell development include not only the acquisition of T-cell characteristics but also programmed loss of potentials for B, natural killer, and dendritic cell development. Evidence from genetics and cell-transfer studies suggests an order and some components of the mechanisms involved in loss of these options, but some of the interpretations conflict. The conflicts can be resolved by a view that postulates overlapping windows of developmental opportunity and individual mechanisms regulating progression along each pathway. This view is consistent with molecular evidence for the expression patterns of positive regulators of non-T developmental pathways, SCL, PU.1 and Id2, in early thymocytes. To some extent, overexpression of such regulators redirects thymocyte development in vitro. Specific commitment functions may normally terminate this developmental plasticity. Both PU.1 overexpression and stimulation of ectopically expressed growth factor receptors can perturb T- and myeloid/dendritic-cell divergence, but only in permissive stages. A cell-line system that approximates DN3-stage thymocytes reveals that PU.1 can alter specification even in a homogeneous population. However, the response of the population to PU.1 is sharply discontinuous. These studies show a critical role for regulatory context in restricting plasticity, which is probably maintained by interacting transcription factor networks.

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