# Hedgehog signaling at the cell's antenna: Smoothened and the primary cilium

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $450,962

## Abstract

ABSTRACT
Hedgehog signaling is a means of intercellular communication that, in vertebrates, relies on immotile cellular
appendages called primary cilia. In our previous work, we discovered that vertebrate Hedgehog signals move
Smoothened to primary cilia, that this movement is necessary for Smoothened activity, and that certain cancers
depend on their cilia for constitutively active Hedgehog pathway activity.
Despite these insights into Hedgehog signaling, how Smoothened movement to cilia is regulated and how ciliary
Smoothened activates the downstream pathway remain unclear. In this renewal application, we examine the
molecular mechanisms by which the Hedgehog receptor, Patched1, controls Smoothened activity (Aim 1), how
Smoothened is activated within the cilium (Aim 2), and how Smoothened activates its downstream effector, the
transcription factor GLI2 (Aim 3).
We have discovered that the ciliary membrane has a unique lipid composition, and that specific ciliary lipids are
necessary and sufficient to activate mammalian Hedgehog signaling. Therefore, the first two aims focus, in part,
on how Patched1 regulates ciliary lipids and how ciliary lipids control Smoothened activity. These experiments
will help reveal how lipids control signaling, and may identify new therapeutic strategies for blocking Hedgehog
pathway-related cancer formation. How Smoothened communicates to GLI2 remains unknown. We have created
a biochemically tractable knock-in Gli2 allele that will allow us to uncover mechanisms by which cilia regulate
GLI2 activity in embryogenesis and oncogenesis.
Thus, the proposed experiments use a combination of mammalian genetic, cell biological, imaging and
biochemical approaches to reveal how the Hedgehog signal transduction pathway uses cilia to transmit
information, both in development and disease.

## Key facts

- **NIH application ID:** 10877972
- **Project number:** 5R01AR054396-17
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Jeremy F Reiter
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $450,962
- **Award type:** 5
- **Project period:** 2007-07-15 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10877972

## Citation

> US National Institutes of Health, RePORTER application 10877972, Hedgehog signaling at the cell's antenna: Smoothened and the primary cilium (5R01AR054396-17). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10877972. Licensed CC0.

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