# Signaling Pathways in Skin Patterning and Polarity

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2021 · $326,375

## Abstract

SIGNALING PATHWAYS IN SKIN PATTERNING AND POLARITY
PROJECT SUMMARY
A major challenge in developmental biology is to understand how single cells are coordinated with one
another to establish their orientations with respect to tissue and body axes. The coordination of neighboring
cells in the plane of tissue is called tissue polarity or planar cell polarity (PCP). PCP is involved in various
developmental processes, and defects in PCP cause many developmental disorders in humans.
Increasing evidence also suggests that PCP is involved in certain cancers. The long-term goal of our study
is to uncover fundamental mechanisms of mammalian PCP in normal development and disease. In this
proposal, we address several unanswered central questions in the PCP field by elucidating mechanisms
of Frizzled6 (Fz6), a key membrane PCP protein that controls the polarity of mouse skin. In preliminary
studies, we discovered: (1) overexpression of Wnt5a, a member of the Wnt family of ligands for Fz
receptors, disrupts hair follicle orientations; (2) knockout of Fz6 results in significant transcriptional changes
in the skin; (3) Astrotactin-2 (Astn2), a recently identified genetic modifier of Fz6, binds to Fz3 and Fz6 in
vitro. Based on available literature and our preliminary data, we hypothesize that Astn2 is a cofactor for
Wnt5a-Fz6 signaling in skin PCP and Fz6 regulates a previously undefined transcriptional network
to establish skin polarity. We will test our hypothesis with the following three aims: (1) to determine if
Wnt ligands, especially Wnt5a, function as orienting cues in Fz6-mediated skin PCP; (2) to elucidate
transcriptional mechanisms governing Fz6-mediated skin PCP; and (3) to elucidate mechanisms of Astn2
in modifying the skin polarity defect in Fz6 knockout mice. The proposed research is innovative. We will
combine unique mouse models that we have generated and a novel in vitro PCP system that we have
developed to elucidate the mechanisms of Fz6 in skin PCP. The proposed research is significant. The
aims will unveil mechanistic insights into several new components in the Fz6-mediated PCP pathway,
including upstream ligands, cofactors, and downstream effectors. Since PCP is a fundamental, conserved
pathway that regulates a wide range of developmental processes, these data will also improve our
understanding of the pathogenesis of PCP-related diseases, such as open neural tube, cleft palate, cystic
kidney disease, hearing loss, ciliopathies, and heart defects.

## Key facts

- **NIH application ID:** 10140381
- **Project number:** 5R01GM129259-03
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Hao Chang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $326,375
- **Award type:** 5
- **Project period:** 2019-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10140381

## Citation

> US National Institutes of Health, RePORTER application 10140381, Signaling Pathways in Skin Patterning and Polarity (5R01GM129259-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10140381. Licensed CC0.

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