Investigating the canonical Wnt signaling pathway in hematopoiesis: revisiting the role of Tcf-1 in early lymphoid development.
Germar, Kristine.
2012
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Abstract: In hematopoiesis, the transcriptional networks governing lineage choice from pluripotent progenitors to mature lymphoid cells remain poorly understood. Although some key factors associated with the specification and commitment of T cells have been described, the functional hierarchy and the roles of key regulators in orchestrating these developmental programs remain unclear. While a loss... read more-of-function model established the importance of T-cell factor 1 (Tcf-1), a T-cell specific mediator of Wnt signaling, in committed T-cell progenitors, I wanted to address how early in lymphoid development Tcf-1 is required. My work has aided in assigning functional significance to Tcf-1 as a gatekeeper of T-cell fate. I show that Tcf-1 is directly activated by Notch signals. Activation of Notch signaling in uncommitted precursors by the thymic stroma is known to initiate the T-cell differentiation program, and I show that Tcf-1 is required at the earliest phase of T-cell determination for progression beyond the early thymic progenitor (ETP) stage. This requirement is cell-intrinsic and Wnt-independent. The global expression profile of Tcf-1 deficient progenitors indicates that basic processes of DNA metabolism are downregulated in its absence, and the blocked T-cell progenitors die by apoptosis. While Tcf-1 is dispensable for the development of bone marrow (BM) progenitors and their migration through the blood, I present evidence for a novel role for Tcf-1 in the early development of natural killer (NK) cells in the BM. Together my data indicate a role for Tcf-1 earlier than previously described and demonstrate multiple roles for Tcf-1 in the roadmap of lymphoid development.
Thesis (Ph.D.)--Tufts University, 2012.
Submitted to the Dept. of Immunology.
Advisors: Fotini Gounari, and Naomi Rosenberg.
Committee: Henry Wortis, and Thereza Imanishi-Kari.
Keyword: Immunology.read less - ID:
- cf95jp92h
- Component ID:
- tufts:20342
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- DCA Citation Guide EndNote
