Investigating the canonical Wnt signaling pathway in hematopoiesis: revisiting the role of Tcf-1 in early lymphoid development.
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... read moreloss-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
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