# Mechanisms of Wg/Wnt regulation by glypican Dlp

> **NIH NIH R00** · UNIVERSITY OF MASSACHUSETTS LOWELL · 2024 · $249,000

## Abstract

PROJECT SUMMARY
 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
tumors.
 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.

## Key facts

- **NIH application ID:** 10974072
- **Project number:** 4R00GM141414-03
- **Recipient organization:** UNIVERSITY OF MASSACHUSETTS LOWELL
- **Principal Investigator:** Indrayani Waghmare
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $249,000
- **Award type:** 4N
- **Project period:** 2022-01-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10974072

## Citation

> US National Institutes of Health, RePORTER application 10974072, Mechanisms of Wg/Wnt regulation by glypican Dlp (4R00GM141414-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10974072. Licensed CC0.

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