# Deciphering Wnt-Ror signaling in cytoskeletal regulation and tissue shape control

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2020 · $392,500

## Abstract

A long-standing question in biology concerns how tissues and organs acquire their stereotyped shape during
development. The Wnt5a-Ror signaling pathway is a master regulator of embryonic tissue morphogenesis, and
deregulation of the pathway has been found to cause a broad range of human pathological conditions,
including the congenital disorders Robinow syndrome and Brachydactyly Type B, as well as cancer metastasis.
In contrast to most well characterized developmental signaling pathways that function via gene transcription,
the Wnt5a-Ror pathway functions through cytoskeletal regulation to control key morphogenetic cell behaviors,
such as cell migration, polarization and adhesion. However, the molecular mechanisms that underlie Wnt5a-
Ror function remain enigmatic. Our research program aims to fill three major gaps in the field: (1) What are the
biochemical interactions that mediate Wnt5a-Ror signal processing and propagation within cells? (2) How does
Wnt5a-Ror signaling engage the cytoskeleton to control morphogenetic cell behaviors? (3) How do these
Wnt5a/Ror-driven processes ultimately control tissue morphogenesis in vivo? To this end, we have integrated
mouse genetics and comparative proteomics to construct the first extended inventory of Wnt5a-Ror pathway
components. This work not only provided crucial insights into the molecular mechanism of Wnt5a-Ror signal
transduction, but also identified Kif26b (a member of the kinesin microtubule motor family) as a critical
cytoskeletal effector of the pathway. Through gain- and loss-of-function studies, we demonstrated that Kif26b
mediates the ability of the Wnt5a-Ror pathway to control cell migration, and that this function of Kif26b is
conserved from C. elegans to humans. Mechanistically, we have established the key finding that Wnt5a-Ror
signaling controls the cellular steady-state concentration of Kif26b via a mechanism involving the ubiquitin-
proteasome system. Using this novel Wnt5a-Ror-Kif26b signaling paradigm, we have successfully developed a
reporter assay that for the first time, allows for quantitative measurement of Wnt5a-Ror signaling activity in live
cells. In this application, we propose to use a combination of protein biochemistry, microscopy and genetics to
elucidate the molecular mechanism linking Ror receptor activation to Kif26b degradation, the cell biological
mechanism underlying Kif26b regulation of cytoskeletal dynamics and cell migration, and the in vivo role of the
Wnt5a-Ror-Kif26b signaling cassette in embryonic tissue morphogenesis. Moreover, we will pair our Wnt5a-
Ror signaling reporter with large-scale CRISPR/Cas9-based genetic screens to identify additional constituents
of the pathway. The successful completion of the project will (1) provide the first detailed molecular portrait of
the Wnt5a-Ror signaling network, (2) reveal the cell biological mechanisms by which Wnt5a-Ror signaling
regulates cytoskeletal dynamics and tissue morphogenesis, and (3) suggest novel bi...

## Key facts

- **NIH application ID:** 9985873
- **Project number:** 5R35GM119574-05
- **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:** 2020
- **Award amount:** $392,500
- **Award type:** 5
- **Project period:** 2016-08-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9985873

## Citation

> US National Institutes of Health, RePORTER application 9985873, Deciphering Wnt-Ror signaling in cytoskeletal regulation and tissue shape control (5R35GM119574-05). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/9985873. Licensed CC0.

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