notch3 is dispensable for thymocyte β-selection and notch1-induced t cell leukemogenesisnotch3是可有可无的胸腺细胞β-selection notch1-induced t细胞白血病生成.pdfVIP

Notch3 Is Dispensable for Thymocyte b-Selection and Notch1-Induced T Cell Leukemogenesis 1,2 1,2 1 1 1 1 Sara Suliman , Joanne Tan , Keli Xu , Philaretos C. Kousis , Paul E. Kowalski , Greg Chang , Sean E. Egan1,3, Cynthia Guidos1,2* 1 Program in Stem Cell and Developmental Biology, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada, 2 Department of Immunology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada, 3 Department of Molecular Genetics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada Abstract Notch1 (N1) signaling induced by intrathymic Delta-like (DL) ligands is required for T cell lineage commitment as well as self- renewal during ‘‘b-selection’’ of TCRb+ CD42CD82 double negative 3 (DN3) T cell progenitors. However, over-expression of the N1 intracellular domain (ICN1) renders N1 activation ligand-independent and drives leukemic transformation during b- selection. DN3 progenitors also express Notch3 (N3) mRNA, and over-expression of ligand-independent mutant N3 (ICN3) influences b-selection and drives T cell leukemogenesis. However, the importance of ligand-activated N3 in promoting b- selection and ICN1-induced T cell leukemogenesis has not been examined. To address these questions we generated mice lacking functional N3. We confirmed that DN3 progenitors express N3 protein using a N3-specific antibody. Surprisingly however, N3-deficient DN3 thymocytes were not defective in generating DP thymocytes under steady state conditions or in more stringent competition assays. To determine if N3 co-operates with N1 to regulate b-selection, we generated N1;N3 compound mutants. However, N3 deficiency did not exacerbate the competitiv