# Molecular Mechanism of Wnt/Planar Cell Polarity Signaling

> **NIH NIH R01** · HARVARD MEDICAL SCHOOL · 2020 · $513,541

## Abstract

Molecular Mechanism of Wnt/Planar Polarity Signaling
Summary
 Directed cellular polarization as a key feature of organismal development is required for tissue and organ
function and homeostasis. Planar Cell Polarity (PCP) is emerging as a fundamental mechanism regulating
various morphogenetic processes including cartilage elongation in the limb, anterior-posterior (A-P) body axis
elongation, neural tube closure, body hair orientation, orientation of inner ear sensory hair cells, left-right
asymmetry and axon guidance in vertebrates. Mutations in PCP signaling components have been identified in
human diseases such as brachydactyly type B1, Robinow syndrome, scoliosis, spinal bifida and epilepsy.
Despite the fundamentally important roles of PCP, the mechanisms of PCP establishment by global instructive
cues such as Wnts remain poorly understood and represent an exciting frontier in developmental and cell
biology. The Wnt/Planar Cell Polarity (PCP) pathway is evolutionarily conserved and provides essential
directional information during morphogenesis to orient cytoskeleton, cell division, cell migration, differential
adhesion across cells, and to position cell extensions, such as cilia and axons. However, unlike the extensively
studied Wnt/β-catenin pathway, Wnt signal transduction in the PCP pathway remains poorly understood. The
PCP pathway is controlled by core PCP proteins including Van Gogh (Vang), Frizzled (Fzd) and Dishevelled
(Dvl), which were originally identified in Drosophila. Wnt/PCP signaling in vertebrates is more complex and
functionally diverse and vertebrate-specific features of PCP require rigorous genetic and biochemical studies of
their own. The core PCP proteins are initially randomly distributed in the cell and gradually accumulate on one
side of the cells instructed by global cues during PCP establishment. Wnt5a is a global cue required for
establishing PCP in vertebrate long bone cartilage by inducing a novel receptor complex that contains Vang
like 2 (Vangl2) and Ror2, a vertebrate specific PCP component. As a result, Vangl2 is phosphorylated in a
Wnt5a dose-dependent manner and Vangl2 phosphorylation regulates its function. Our identification of Wnt
induced PCP signalosome and Vangl2 phosphorylation as both an important readout and transducer of
Wnt/PCP signaling opens a new door to find missing links in the Wnt/PCP signaling cascade. We propose to
decipher novel Wnt5a signaling events that eventually lead to PCP establishment with rigorous genetic and
biochemical approaches. In Specific Aim 1, we will define the functions and regulations of Vangl2
phosphorylation in vivo. In Specific Aim 2, we will define the molecular mechanism whereby Wnt5a signal is
transduced through Vangl2 in the PCP pathway. In Specific Aim 3, we will identify additional regulatory
components in Wnt/PCP signaling. Given the fundamental roles of Wnt/PCP signaling in many morphogenetic
processes and identified WNT5A, VANGL and ROR2 mutations in human d...

## Key facts

- **NIH application ID:** 9838727
- **Project number:** 5R01AR070877-04
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Yingzi Yang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $513,541
- **Award type:** 5
- **Project period:** 2017-02-07 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9838727

## Citation

> US National Institutes of Health, RePORTER application 9838727, Molecular Mechanism of Wnt/Planar Cell Polarity Signaling (5R01AR070877-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9838727. Licensed CC0.

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