# Molecular dissection of the ciliary gate

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2022 · $357,750

## Abstract

Project Summary
Cilia serve as sensory devices on most eukaryotic cells surface and play an essential role in development.
Ciliary assembly via intraflagellar transport (IFT) and sensory transduction capabilities are highly conserved in
all ciliated organisms. With rapid advancements in the positional cloning of human disease genes in the past
decade, a wide variety of disorders such as autosomal dominant polycystic kidney disease (ADPKD) have
been characterized molecularly as ciliopathies. Consistent with the ubiquitous presence of cilia, many
ciliopathies occur as syndromic disorders that affect multiple organs, including the kidney, liver, limb, eye, and
central nervous system. One central question in cilia biology is that how the ciliary gate functionally separates
the cilium from the cell body and makes it a discrete sensing organelle. During ciliogenesis, the distal
appendages of the mother centriole transform to transition fibers (TFs), which form a 9-bladed propeller
structure connecting the basal body to the ciliary base membrane. The distinct subcellular location of TFs
makes it a good candidate for the ciliary gate. Nonetheless, the paramount challenges being that molecular
insights about the establishment, either structural or functional, of TFs as the ciliary gate remain poorly defined.
Due to the essential roles of cilia in mammalian embryonic development, the study of the connections between
cilia and disease are extremely difficult in mammalian models. Thus, alternative experimental systems are
necessary. Caenorhabditis elegans has been established as an effective model for characterizing the
physiological roles of ciliary proteins in their native cellular environments that is relevant for understanding
mammalian biology due to the highly conserved cilia composition and signaling. We pioneered the application
of C. elegans as a model to study the biological importance of TFs. Our preliminary studies show that DYF-19
physically associates with different players to regulate distinct cilia gating: with the DYF-19-TALPID-3-ANK-26
functional module in regulating IFT import, whereas DYF-19-CCDC-85 module in regulating gating for
membrane proteins. On the other hand, HYLS1 coordinate with GAS8 to regulate the establishment of the
ciliary gate. We also retrieved novel worm mutants with likely disrupted TF integrity in a forward genetic
screening. Furthermore, our initial studies suggested that the key discoveries made in C. elegans are highly
conserved in mammalian cells. In this proposal, we will determine the full components and activities of
underlying pathways so that the fundamental roles of the ciliary gate in the context of cilia and ciliopathies are
better understood. We plan to achieve this goal by pursuing three specific questions: i), how cilia gating is
achieved? ii) how the ciliary gate is established? and iii) if the core pathways for the ciliary gate are
conserved in mammalian cells? By combining C. elegans with mammalian s...

## Key facts

- **NIH application ID:** 10409656
- **Project number:** 5R01DK099160-09
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Jinghua Hu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $357,750
- **Award type:** 5
- **Project period:** 2014-08-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10409656

## Citation

> US National Institutes of Health, RePORTER application 10409656, Molecular dissection of the ciliary gate (5R01DK099160-09). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10409656. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*