merrillb@uic.edu
Research Interests:
Each of the trillions of cells in your body is
derived from a single stem cell, the fertilized
egg. By dynamically responding to their cellular
surroundings, the progeny of this stem cell follow
the blueprint encoded by the genome to construct
the basic structure of the body, to form tissues
and organs, and to maintain physiological systems
throughout your lifetime.
In the Merrill lab, we endeavor to reveal fundamental
molecular mechanisms driving cell fates decisions,
and how these decisions direct embryogenesis and
stem cell maintenance in vivo. We center our efforts
on the roles of a family of DNA-binding transcriptional
regulators called Tcf/Lef factors. Tcf/Lef proteins
can either activate or repress transcription of
target genes depending upon the cohort of physically
interacting proteins available to interact with
a Tcf/Lef protein within a given cell (see figure
below).
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Dr. Brad Merrill, Assistant
Professor
Doctoral Training
,Ph.D
Biological Sciences,
1999
University of California,San
Diego
(Advisor:Dr. Connie
Holm)
Postdoctoral Training,1999-2004
University of Chicago
and
The Rockefeller
University, New York
(Advisor:Dr. Elaine
Fuchs)
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By examining Tcf/Lef knockout and tissue-specific knockout
mice, we have identified physiological processes controlled
by Tcf/Lef factors. Furthermore, by utilizing in vitro
stem cell systems and knockin mutations affecting specific
protein-protein interactions, we have begun to unravel
the molecular mechanisms that drive these interesting
and important cell fate decisions in vivo.
Currently Highlighted Research
Directions:
Mechanisms of Tcf3-mediated cell fate decisions during
embryogenesis
The early mouse embryo exhibits radial symmetry until
approximately embryonic day 6.5, when a cell fate change
in a group of cells defines the future posterior and
thus the anteroposterior axis of the body. Previously,
WNTs have been shown to induce this body axis, yet a
requirement for a Tcf/Lef protein had not been discovered
until we knocked out the Tcf3 gene. Tcf3-/- mutants
form striking duplications of the body axis  such
as the tail-head-tail duplications shown here. Further
analysis of the defects in Tcf3-/- embryos will elucidate
how multiple signaling pathways combine to induce an
embryonic axis.
Creating a Tcf3 knockin mutant (DeltaNTcf3),
incapable of binding beta-catenin, formally tests whether
Tcf3-mediated activation or repression of target genes
is required during embryogenesis. Since Tcf3deltaN/deltaN
knockin mutants embryos develop with a normal body axis,
beta-catenin binding must not be required for Tcf3 function
during early embryonic stages, and Tcf3 must repress
target genes to prevent axis duplication. Interestingly,
Tcf3deltaN/deltaN mice die soon after birth and exhibit
craniofacial structural defects. Analysis of the morphogenetic
defects in the Tcf3deltaN/deltaN mouse is currently
underway and has potential to definitively identify
the first physiological requirements for Tcf3-?-catenin
interaction in any organism
Roles of Tcf/Lef factors in regulating
stem cell fates:
Recently, scientists and the general public alike have
realized the importance of understanding basic principles
of stem cell biology and the mechanisms by which stem
cells self renew. Tcf3 is expressed in multiple stem
cell types (hematopoietic, neural, embryonic, hair follicle).
In addition, WNT stimulation of hematopoietic stem cells
directly activates their self renewal. Interestingly,
we have found that compared to Tcf3+/- controls, Tcf3-/-
embryonic stem (ES) cells fail to differentiate, suggesting
that Tcf3 regulates stem cell self renewal. Identifying
the molecular mechanisms and the direct target genes
of Tcf3 that control ES cell fates are crucial for understanding
the basic biology of stem cells. These insights combined
with the ability to remove Tcf3 and beta-catenin from
mouse stem cells in vivo with “conditional”
knockout alleles, together provide a powerful approach
for understanding how stem cells are regulated in their
native environment.
Selected Publications:
Merrill, B.J., Pasolli, A., Polak, L.,
Rendl, M., Garcia-Garcia, M.J., Anderson, K.V., and
Fuchs, E. Tcf3: A transcriptional regulator of axis
induction in the early embryo. Development 131(2): 263-274.
2004
Merrill, B.J., Gat, U., DasGupta, R., and Fuchs E.
Tcf3 and Lef1 regulate lineage differentiation of multipotent
stem cells in skin. Genes Dev. 15(13): 1688-1705. 2001
Fuchs, E., Merrill, B.J., Jamora, C., and DasGupta,
R. At the roots of a never-ending cycle. Developmental
Cell 1: 13-25. 2001
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