# Wnt/Frizzled-PCP signaling in development and disease

> **NIH NIH R35** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2022 · $607,529

## Abstract

Epithelial cells are polarized in two axes for their function, ubiquitous apical-basal polarity and a second axis
within the epithelial plane, referred to as Planar Cell Polarity (PCP). Cell polarity and ordered cellular patterning
during organ development and homeostasis depend on PCP mechanisms. Classical PCP examples include in
Drosophila adult cuticular structures. Similarly, in mammals striking aspects of PCP are evident in the skin, the
inner ear epithelium, or the respiratory system and most other internal organs. Moreover, convergent extension
processes during gastrulation and neural tube closure requires PCP signaling, and the PCP pathway is linked
to the regulation of asymmetric cell divisions in stem cells of many organs. Studies of PCP establishment in
Drosophila serve as a paradigm to unravel this type of polarity in development and human disease. PCP is
coordinated by long-range Wnt ligand signals, resulting in asymmetric localization of their receptors, the
Frizzled (Fz) proteins, and associated signaling cascade. Core Fz/PCP factors are required to interpret polarity
within the cell and relay this to neighboring cells. All core Fz/PCP members are evolutionarily conserved and
regulate all PCP aspects. This Wnt-pathway is distinct from canonical Wnt-Fz/β-catenin signaling (and correct
regulation of signaling specificity between the two Wnt-pathways, activated by the same receptor(s), is critical
for development and disease). In Wnt-PCP-signaling Fz's act both, as receptors for Wnts and ligands for its
intercellular binding partner(s) Van Gogh/Vang (Vangl1/2 in mammals). The cellular mechanism(s) affecting
polarity downstream of either Fz or Vang upon polarized localization remain very poorly understood. The scope
and focus of my lab's research and this application is to investigate the mechanistic interactions of long-range
PCP signaling and the resulting cell biological read-outs and intracellular responses. Our recent focus has
been/is on Vang/Vangl function, as a result of its intercellular interaction with Fz, and the associated cellular
response. Our work is and will be also guided by patient derived data and the respective functional dissection
of these mutations. Based on exciting ongoing experiments, we will address the physiological significance of
Fz-induced Vang phosphorylation and associated kinase function, and how these affect Vang interactions with
cytoplasmic effectors. These studies will be aided by including patient data with Vangl1/2 associated neural
tube closure defects. In parallel, we are dissecting the intracellular cell biological responses to PCP signaling
and how these affect positioning and the mechanistic interplay with cilia associated proteins, with the
advantage of being able to do so in non-ciliated Drosophila cells. A combination of in vivo studies and cell
culture biochemical experiments will be performed to achieve these goals. The processes of PCP
establishment and Wnt/Fz signaling have been link...

## Key facts

- **NIH application ID:** 10397149
- **Project number:** 5R35GM127103-05
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Marek Mlodzik
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $607,529
- **Award type:** 5
- **Project period:** 2018-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10397149

## Citation

> US National Institutes of Health, RePORTER application 10397149, Wnt/Frizzled-PCP signaling in development and disease (5R35GM127103-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10397149. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*