Wnt signaling is an evolutionarily conserved pathway that regulates several cellular behaviors such as
cell proliferation, survival, differentiation, and migration to promote tissue homeostasis. Of note, the Wg/Wnt
signaling pathway is important for tissue patterning and is often deregulated in epithelial cancers. Secreted Wnt
ligands are distributed in the extracellular space to promote paracrine and long-range signaling in target cells.
These paracrine and long-range functions of Wnts are dependent on extracellular Wnt availability, which in part
is dictated by cell-surface glypican, Dally-like protein (Dlp). In this proposal, I will focus on molecular mechanisms
that dictate Dlp-mediated regulation of Wnt availability and signaling.
Dlp’s role in regulating Wnt signaling has been described as ‘biphasic’: By continual binding and release,
Dlp simultaneously promotes long-range signaling and restricts paracrine signaling, ensuring proper ligand
availability at both ranges. The Page-McCaw lab established Drosophila germarium, a tissue where oogenesis
occurs, as a model to study mechanisms that define Wnt signaling ranges, and identified a novel Dlp/Mmp2
(Matrix Metalloprotease 2) module that modulates paracrine and long-range Wnt signaling in the germarium.
Specifically, I found that proteolytic cleavage of Dlp by Mmp2 alters its subcellular localization and function to
modulate Wnt availability. Additionally, my preliminary data suggest that Dlp/Mmp2 may regulate Wnt signaling
in epithelial tumors to promote tumor growth. In Aim 1, I will investigate the molecular events that occur
downstream of proteolytic cleavage of Dlp to modulate Wg/Wnt availability and signaling in the germarium and
The extracellular Wnt distribution is tightly linked with its production and secretion. I found that Dlp can
modulate Wg (Wnt-1) production in source cells in the germarium. Wg production in source cells in germaria is
tightly regulated and this regulation is crucial for proper oogenesis. Additionally, I found that Dlp interacts with
non-ligand proteins (a finding that has not been previously reported) that communicate with intracellular
cytoskeletal machinery, potentially to modulate cell adhesion and/or shape. In Aim 2, I will investigate novel
mechanisms of how Dlp regulates Wnt ligand production and long-range Wg distribution to facilitate long-range
Wg signaling. These investigations will uncover previously unappreciated roles of cell-surface glypicans in
regulating Wnt signaling and elucidate novel paradigms of developmental strategies employed in multicellular
organisms to maintain tissue homeostasis.