# The role of ciliary trafficking in Hedgehog receptor function

> **NIH NIH R01** · GEORGE WASHINGTON UNIVERSITY · 2021 · $346,115

## Abstract

Project summary/abstract
 The Hedgehog (Hh) signaling pathway plays crucial roles both in embryonic development and in adult
stem cell function. Loss of Hh signaling during development is associated with birth defects, and inappropriate
Hh pathway activation post-embryonically is associated with numerous cancer types. Despite its importance in
development, physiology, and disease, our ability to therapeutically modulate Hh pathway activity is limited by
an incomplete understanding of the mechanisms underlying pathway activation. To this end, a comprehensive
understanding of Hh signal transduction will provide a better basis for the design and implementation of
effective therapeutic approaches to diseases caused by malfunction of the Hh signaling pathway.
 The central mystery of Hh signal transduction is the mechanism by which the Hh receptor Patched
(Ptch1 in mammals) acts to regulate the pathway activity. Mouse genetic studies have recently linked Hh signal
transduction to the primary cilium, a tiny microtubule-based organelle projecting from the cell surface that
senses extracellular signals and is associated with a number of human diseases collectively termed
ciliopathies. Studies from several groups, including ours, show that Hh pathway components continuously
traffic through the cilium. In the absence of Hh, the Ptch1 receptor localizes to the primary cilium, where it
inhibits Smoothened (Smo) activation and prevents Smo accumulation in the cilia. When Hh binds to Ptch1,
however, Ptch1 activity is blocked and Ptch1 leaves the cilium, leading to the accumulation of Smo in the
cilium and activation of downstream signaling pathways. Ciliary enrichment of these key components of the Hh
pathway, as well as their dynamic localization in response to the Hh ligand, lead us to propose that ciliary
trafficking of Hh pathway proteins is crucial for Ptch1's regulation of Smo.
 The proposed project will elucidate the mechanism of Hh receptor function in the context of primary
cilium by: (1) defining critical motifs required for Ptch1/Smo ciliary trafficking using structured illumination
microscopy; (2) examining of the ciliary entry and exit kinetics of Ptch1 and Smo during Hh pathway activation
with a photoconversion assay in live cells; and (3) defining the cellular factors required for Ptch1/Smo ciliary
trafficking using a newly adapted biochemical (BioID) approach.
 Our findings will provide a paradigm for understanding how the Hh receptor functions, as well as a
basis for the design and implementation of effective approaches to therapeutically modulate Hh pathway
activity. Our findings will also illuminate cellular and molecular mechanisms underlying polycystic kidney
disease, obesity, deafness, and other conditions associated with human ciliopathies.

## Key facts

- **NIH application ID:** 10113633
- **Project number:** 5R01GM117440-05
- **Recipient organization:** GEORGE WASHINGTON UNIVERSITY
- **Principal Investigator:** Xiaoyan Zheng
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $346,115
- **Award type:** 5
- **Project period:** 2017-05-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10113633

## Citation

> US National Institutes of Health, RePORTER application 10113633, The role of ciliary trafficking in Hedgehog receptor function (5R01GM117440-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10113633. Licensed CC0.

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