# Function and regulatory mechanisms of the Wnt5a-Ror morphogenetic pathway

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2023 · $431,258

## Abstract

Project Summary/Abstract
Wnt5a-Ror signaling is an evolutionarily conserved developmental signaling pathway that controls
morphogenetic cell and tissue behavior. Misregulation of the pathway in vertebrates results in profound tissue
elongation defects, including shortening and widening of the body axis, limbs, and face. In humans, mutations
in key nodes of the pathway, including the WNT5A ligand, the ROR2 and Frizzled (FZD2) co-receptors, and the
cytoplasmic signal transducers Dishevelled (DVL) 1 and DVL3, give rise to Robinow syndrome, a congenital
disorder with highly similar tissue elongation phenotypes. Notably, bulldogs exhibit similar physical
characteristics and carry a mutation in DVL2, analogous to the human mutations in DVL1 and DVL3, that reduces
its capacity to respond to Wnt5a-Ror signals. Despite its physiological and clinical importance, the biochemical
steps and cytoskeletal mechanisms that mediate Wnt5a-Ror signaling remain largely uncharacterized;
consequently, insights into the disease mechanism(s) driving Robinow syndrome are unknown. The overarching
goal of our research is to dissect Wnt5a-Ror pathway function and regulation at the biochemical, cellular and
organismal levels. Specifically, we ask in this proposal: 1) How does the Ror/FZD co-receptor complex transmit
Wnt5a signals at the cell surface, and how do pathogenic mutations in ROR2 alter receptor complex function?
2) How do Dvl scaffolding proteins relay Wnt5a-Ror signals in the cytosol, and how do mutations in human DVL1
and DVL3 and canine DVL2 disrupt DVL function? 3) How does the Wnt5a-Ror pathway engage the cytoskeleton
to alter cell behavior and biomechanics, and how do disease mutations in the pathway perturb these processes?
To address these questions, we have developed novel reporter assays that enable quantitative measurement of
Wnt5a-Ror signaling activity in live cells. We have also developed a highly physiological cell culture system in
which we can readily knock out and re-express proteins of interest at near-endogenous levels to rescue signaling.
Using this approach, we will conduct detailed ROR2 and DVL structure-function analyses to identify the structural
elements and mechanisms required for these proteins’ respective functions. These experiments will be
complemented by protein binding studies to define ROR2 and DVL protein interaction networks and how their
disruption contributes to disease pathogenesis. To elucidate the cell biological function of the pathway, we have
optimized 2D and 3D culture systems for cell behavioral analyses and identified a critical role for Wnt5a-Ror
signaling in controlling cell migration, stress fiber stabilization and actomyosin-based contractility. These
observations coincide with biochemical and subcellular localization changes in the RhoA-MLC-actomyosin
regulatory network. We will conduct pharmacological and genetic perturbation experiments to dissect the
function of this network in normal and pathogenic Wnt5a-Ror-di...

## Key facts

- **NIH application ID:** 10558623
- **Project number:** 5R35GM144341-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Hsin-Yi Henry Ho
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $431,258
- **Award type:** 5
- **Project period:** 2022-02-01 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10558623

## Citation

> US National Institutes of Health, RePORTER application 10558623, Function and regulatory mechanisms of the Wnt5a-Ror morphogenetic pathway (5R35GM144341-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10558623. Licensed CC0.

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