Productive rearrangement of TCR-beta genes at the CD44- CD25+ (DN3) stage of thymocyte development and assembly with the invariant pre-TCR-alpha and CD3 subunits leads to the formation of a pre-TCR complex on the cell surface. Cell autonomous and ligand independent pre-TCR signaling triggers a complex cascade of signaling events leading to the survival, proliferation and differentiation of immature thymocytes. One of the cascades that play an essential role in the stages following the onset of pre-TCR activity is the wnt/beta-catenin pathway. Beta-catenin is the central mediator of wnt signaling, whose stabilization in response to activation of this pathway results to its transport to the nucleus, where it binds to and activates the TCF/LEF transcription factors. Deficiency for both TCF-1, and LEF-1, lymphocyte specific beta-catenin regulated transcription factors, results in a complete block of fetal thymocyte development in fetal thymic organ cultures (FTOC) at the immature single positive stage. Interaction of beta-catenin with TCF-1 is necessary for the action of this protein during the DN to DP transition, and somatic stabilization of beta-catenin can mediate developmental progression in the absence of pre-TCR and ab-TCR signaling. The exact mechanism of function as well as the molecular components and specific targets of the wnt/beta-catenin pathway involved in this developmental stage remain to be elucidated. In view of the fact that this developmental transition depends on pre-TCR signaling it becomes important to specifically examine the interaction between the pre-TCR and the wnt/beta- catenin signaling cascades. The present proposal focuses at dissecting the requirement for wnt/beta-catenin signaling in the DN to DP thymocyte transition as well as determining the interaction between pre-TCR and wnt/beta-catenin signaling cascades.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI059676-02
Application #
6868943
Study Section
Immunobiology Study Section (IMB)
Program Officer
Macchiarini, Francesca
Project Start
2004-04-01
Project End
2009-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
2
Fiscal Year
2005
Total Cost
$366,750
Indirect Cost
Name
Tufts University
Department
Type
DUNS #
079532263
City
Boston
State
MA
Country
United States
Zip Code
02111
Germar, Kristine; Dose, Marei; Konstantinou, Tassos et al. (2011) T-cell factor 1 is a gatekeeper for T-cell specification in response to Notch signaling. Proc Natl Acad Sci U S A 108:20060-5
Khazaie, Khashayarsha; Blatner, Nichole R; Khan, Mohammad Wasim et al. (2011) The significant role of mast cells in cancer. Cancer Metastasis Rev 30:45-60
Dose, Marei; Sleckman, Barry P; Han, Jin et al. (2009) Intrathymic proliferation wave essential for Valpha14+ natural killer T cell development depends on c-Myc. Proc Natl Acad Sci U S A 106:8641-6
Kovalovsky, Damian; Yu, Yu; Dose, Marei et al. (2009) Beta-catenin/Tcf determines the outcome of thymic selection in response to alphabetaTCR signaling. J Immunol 183:3873-84
Dose, Marei; Gounari, Fotini (2009) The My(c)stery of iNKT cell ontogeny. Cell Cycle 8:3082-5
Gounaris, Elias; Erdman, Susan E; Restaino, Clifford et al. (2007) Mast cells are an essential hematopoietic component for polyp development. Proc Natl Acad Sci U S A 104:19977-82
Guo, Zhuyan; Dose, Marei; Kovalovsky, Damian et al. (2007) Beta-catenin stabilization stalls the transition from double-positive to single-positive stage and predisposes thymocytes to malignant transformation. Blood 109:5463-72
Mao, Changchuin; Tili, Esmerina G; Dose, Marei et al. (2007) Unequal contribution of Akt isoforms in the double-negative to double-positive thymocyte transition. J Immunol 178:5443-53
Dose, Marei; Khan, Irum; Guo, Zhuyan et al. (2006) c-Myc mediates pre-TCR-induced proliferation but not developmental progression. Blood 108:2669-77
Gounari, Fotini; Chang, Rui; Cowan, Janet et al. (2005) Loss of adenomatous polyposis coli gene function disrupts thymic development. Nat Immunol 6:800-9