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Michie AM , Chan AC , Ciofani M , Carleton M , Lefebvre JM , He YP , Allman DM , Wiest DL , Zuniga-Pflucker JC , Izon DJ
Constitutive Notch signalling promotes CD4(-)CD8(-) thymocyte differentiation in the absence of the pre-TCR complex, by mimicking pre-TCR signals
International Immunology. 2007 Dec;19(12) :1421-1430
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Notch1 signalling is essential for the commitment of multipotent lymphocyte precursors towards the alpha beta T-cell lineage and plays an important role in regulating beta-selection in CD4(-)CD8(-) double-negative (DN) thymocytes. However, the role played by Notch in promoting the development of CD4(+)CD8(+) double-positive (DP) thymocytes is poorly characterized. Here, we demonstrate that the introduction of a constitutively active Notch1 (ICN1) construct into RAG(-/-) lymphocyte precursors resulted in the generation of DP thymocytes in in vitro T-cell culture systems. Notably, developmental rescue was dependent not only on the presence of an intact Notch1 RAM domain but also on Delta-like signals, as ICN1-induced DP development in RAG(-/-) thymocytes occurred within an intact thymus or in OP9-DL1 co-cultures, but not in OP9-control co-cultures. Interestingly, ICN1 expression in SLP-76(-/-) precursors resulted in only a minimal developmental rescue to the immature CD8(+)!
Michie, Alison M. Chan, Angela C. Ciofani, Maria Carleton, Michael Lefebvre, Juliette M. He, Yiping Allman, David M. Wiest, David L. Zuniga-Pfluecker, Juan Carlos Izon, David J. OXFORD UNIV PRESS