# Intraflagellar Transport Proteins in Mice

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2020 · $422,527

## Abstract

Project Summary / Abstract
The primary cilium is critical to vertebrate development and the prevention of disease. Severe defects in this
organelle lead to prenatal lethality in extreme cases and a variety of structural birth defects and degenerative
diseases in less extreme cases. It is thought that the primary cilium serves as a cellular antenna to monitor the
extracellular environment and feed information back to the cell to coordinate its action with that of the
surrounding cells. A large number of signaling pathways are directly or indirectly regulated by cilia but of these,
hedgehog is particularly important in vertebrate development. Understanding how the cilium is assembled and
how the signaling environment is created and maintained is critical to understanding how this organelle
functions in the etiology of human diseases. The cilium is assembled by the process of intraflagellar transport
(IFT) where large protein complexes called IFT particles are carried along the ciliary microtubules by kinesin
and dynein motors. These large complexes transport proteins made in the cell body into the cilium to build and
maintain the structure. In addition to building cilia it is now clear that IFT is an integral part of hedgehog and
other ciliary signal transduction cascades.
 The propagation of the hedgehog signal involves a complex set of dynamic movements of receptors and
effectors into and out of cilia. We found that Ift25 and Ift27, two components of the IFT system, are not required
for ciliary assembly but are required for hedgehog signaling. In their absence, hedgehog receptors fail to be
removed from cilia at appropriate times during signaling and transcription factors are mislocalized. Under
normal conditions, activation of the pathway is initiated by hedgehog ligand binding to a ciliary-localized
receptor called Ptch1. This causes Ptch1 to exit the cilium and relieves a negative inhibition on a second
receptor called Smo. Activation of Smo causes it to accumulate in cilia and this drives a third receptor, Gpr161,
out of cilia. The Gli transcription factors then accumulate at the ciliary tip and become activated before moving
into the nucleus to regulate gene expression. When Ift25/Ift27 are missing, Ptch1 and Gpr161 fail to be
removed from cilia upon pathway activation, Smo is inappropriately localized to cilia when the pathway is
inactive and the Gli transcription factors are not concentrated at the ciliary tip upon pathway activation. Our
current proposal seeks to understand how Ift25/Ift27 in conjunction with the rest of the IFT system regulates
the removal of the hedgehog receptors at the appropriate times during signaling. Emerging evidence suggests
that hedgehog receptors are ubiquitinated in pathway dependent manner. Our preliminary evidence indicates
that Ift25/Ift27 remove ubiquitinated Smo from cilia. This suggests a model where hedgehog signaling
regulates ubiquitination of the hedgehog receptors and this in turn controls their in...

## Key facts

- **NIH application ID:** 9858347
- **Project number:** 5R01GM060992-19
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Gregory J Pazour
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $422,527
- **Award type:** 5
- **Project period:** 2001-06-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9858347

## Citation

> US National Institutes of Health, RePORTER application 9858347, Intraflagellar Transport Proteins in Mice (5R01GM060992-19). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9858347. Licensed CC0.

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