Pre-TCR signaling inactivates Notch1 transcription by antagonizing E2A
Y Yashiro-Ohtani, Y He, T Ohtani… - Genes & …, 2009 - genesdev.cshlp.org
Y Yashiro-Ohtani, Y He, T Ohtani, ME Jones, O Shestova, L Xu, TC Fang, MY Chiang…
Genes & development, 2009•genesdev.cshlp.orgPrecise control of the timing and magnitude of Notch signaling is essential for the normal
development of many tissues, but the feedback loops that regulate Notch are poorly
understood. Developing T cells provide an excellent context to address this issue. Notch1
signals initiate T-cell development and increase in intensity during maturation of early T-cell
progenitors (ETP) to the DN3 stage. As DN3 cells undergo β-selection, during which cells
expressing functionally rearranged TCRβ proliferate and differentiate into CD4+ CD8+ …
development of many tissues, but the feedback loops that regulate Notch are poorly
understood. Developing T cells provide an excellent context to address this issue. Notch1
signals initiate T-cell development and increase in intensity during maturation of early T-cell
progenitors (ETP) to the DN3 stage. As DN3 cells undergo β-selection, during which cells
expressing functionally rearranged TCRβ proliferate and differentiate into CD4+ CD8+ …
Precise control of the timing and magnitude of Notch signaling is essential for the normal development of many tissues, but the feedback loops that regulate Notch are poorly understood. Developing T cells provide an excellent context to address this issue. Notch1 signals initiate T-cell development and increase in intensity during maturation of early T-cell progenitors (ETP) to the DN3 stage. As DN3 cells undergo β-selection, during which cells expressing functionally rearranged TCRβ proliferate and differentiate into CD4+CD8+ progeny, Notch1 signaling is abruptly down-regulated. In this report, we investigate the mechanisms that control Notch1 expression during thymopoiesis. We show that Notch1 and E2A directly regulate Notch1 transcription in pre-β-selected thymocytes. Following successful β-selection, pre-TCR signaling rapidly inhibits Notch1 transcription via signals that up-regulate Id3, an E2A inhibitor. Consistent with a regulatory role for Id3 in Notch1 down-regulation, post-β-selected Id3-deficient thymocytes maintain Notch1 transcription, whereas enforced Id3 expression decreases Notch1 expression and abrogates Notch1-dependent T-cell survival. These data provide new insights into Notch1 regulation in T-cell progenitors and reveal a direct link between pre-TCR signaling and Notch1 expression during thymocyte development. Our findings also suggest new strategies for inhibiting Notch1 signaling in pathologic conditions.
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