title: Pre-TCR signaling inactivates Notch1 transcription by antagonizing E2A.
abstract: 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.
authors: Department of Pathology and Laboratory Medicine, Abramson Family Cancer Research Institute, Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors: Yumi
authors: Y
authors: Yashiro-Ohtani
authors: Yiping
authors: Y
authors: He
authors: Takuya
authors: T
authors: Ohtani
authors: Mary E
authors: ME
authors: Jones
authors: Olga
authors: O
authors: Shestova
authors: Lanwei
authors: L
authors: Xu
authors: Terry C
authors: TC
authors: Fang
authors: Mark Y
authors: MY
authors: Chiang
authors: Andrew M
authors: AM
authors: Intlekofer
authors: Stephen C
authors: SC
authors: Blacklow
authors: Yuan
authors: Y
authors: Zhuang
authors: Warren S
authors: WS
authors: Pear
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002460:Cell Line; D015536:Down-Regulation; D005786:Gene Expression Regulation; D019674:Genes, T-Cell Receptor beta / Q000235:genetics / Q000502:physiology*; D018398:Homeodomain Proteins / Q000378:metabolism; D051796:Inhibitor of Differentiation Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D051796:Inhibitor of Differentiation Proteins; D012333:RNA, Messenger; D051881:Receptor, Notch1; C491539:Bhlhe40 protein, mouse; C497762:Notch1 protein, mouse; C075668:Tcf3 protein, mouse; C067679:Idb3 protein, mouse