Details

Autor(en) / Beteiligte

• Yashiro-Ohtani, Yumi
• He, Yiping
• Ohtani, Takuya
• Jones, Mary E
• Shestova, Olga
• Xu, Lanwei
• Fang, Terry C
• Chiang, Mark Y
• Intlekofer, Andrew M
• Blacklow, Stephen C
• Zhuang, Yuan
• Pear, Warren S

Titel

Pre-TCR signaling inactivates Notch1 transcription by antagonizing E2A

Ist Teil von

• Genes & development, 2009-07, Vol.23 (14), p.1665-1676

Ort / Verlag

United States: Cold Spring Harbor Laboratory Press

Erscheinungsjahr

2009

Link zum Volltext

Quelle

EZB Free E-Journals

Beschreibungen/Notizen

• 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 beta-selection, during which cells expressing functionally rearranged TCRbeta 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-beta-selected thymocytes. Following successful beta-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-beta-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.