Sandra Zimmerman
Mellon
Institute
Room 604
Department of Biological
Sciences
Carnegie Mellon University
4400 Fifth Avenue
Pittsburgh, PA 15213
Lab Phone: (412) 268-9820
Email: szimmerm@andrew.cmu.edu
Ph.D. Biology, Carnegie Mellon University
B.S. Nuclear Engineering, Arizona State University
B.A. Music, University of Washington
B.M. Violin Performance, University of Washington
B.S. Nuclear Engineering, Arizona State University
Research:
APC2 APC1 double null clones in the
Drosophila wing imaginal disc.
GFP
(green), adherens junctions indicated by phosphotyrosine immunolocalization
(red), nuclei (blue).
Top
row: APC2+ APC1+
control clones, indicated by lack of GFP. Surrounding tissue (with GFP) is APC2+ APC1+.
Middle and bottom rows: APC2 APC1 double null clones, indicated by lack of GFP. Surrounding tissue (with GFP) is heterozygous (APC2+ APC1+/APC2- APC1-).
Epithelial morphogenesis is driven by coordinated cell shape changes that rely on rearrangements of cytoskeletal architecture. Signal transduction pathways function upstream of morphogenesis, but the molecular connections between signaling and the cytoskeletal dynamics are not well understood. The canonical Wnt signaling pathway has well known roles in specifying cell fate during development, but much less is known about its role in morphogenesis. The tumor suppressor Adenomatous polyposis coli (APC) is a negative regulator of Wnt signaling and functions in cytoskeletal organization. In humans, mutations in APC initiate the formation of colon polyps, and can ultimately lead to cancer.
I am interested in how loss of
APC function leads to morphological changes in epithelial tissue. To this end,
I have generated APC2 APC1 double null clones in the Drosophila wing
imaginal disc. The wing disc is the larval wing primordium, consisting of a
single layer of polarized, columnar epithelial cells. APC2 APC1 double
null clones exhibit cell segregation, inappropriate apical constriction and
invagination. Furthermore, I have shown that these morphological changes are
due to inappropriate activation of the Wnt pathway. Wnt activation has been
reported to upregulate Drosophila E-cadherin expression in wing discs. However,
my data indicates that apical constriction and invagination of APC null
tissue are independent of DE-cadherin upregulation. Instead, in apically
constricting cells, phosphorylated myosin regulatory light chain is enriched in
the apical cortex. Further, the Rho activator RhoGEF2 is cortically and
cytoplasmically enriched in apically constricting cells. I am currently
investigating whether the Rho pathway plays a role in the morphological
transformation in APC null epithelial tissue. Although a connection
between non-canonical Wnt signaling and the Rho pathway is already known, my
data suggests the possibility of a novel link between canonical Wnt signaling
and tissue morphogenesis through activation of the Rho pathway and Myosin II in
the wing imaginal disc.