# Genetic Dissection of Signaling and Cilia

> **NIH NIH R35** · EMORY UNIVERSITY · 2021 · $388,058

## Abstract

Project Summary/Abstract
 Cilia have sparked phenomenal interest in the past decade, after the realization that they are a
fundamental cellular organelle required for signaling. Untangling the specific mechanisms that regulate Sonic
hedgehog (Shh) signaling within the cilium is difficult since so many mutants that disrupt ciliogenesis also
affect Shh signaling. We have identified several mouse mutants disrupting cilia-related genes and Shh
signaling using forward genetic screens aimed at identifying novel genes or new alleles of known genes that
direct neural patterning. Our general strategy is to characterize the in vivo phenotype and then derive cell lines
from the mutant mice to define cellular phenotypes. With knowledge gleaned from our colleagues in
biochemistry and human genetics, we test mutant versions of the proteins, and then select some for in vivo
modeling. Employing exactly this strategy, we have long focused on a small ciliary GTPase, Arl13b, that we
hypothesize integrates the regulation of ciliogenesis and Hh signaling through distinct effectors and their
downstream pathways. As a GTPase, single basepair mutations within the GTPase domain of Arl13b are
predicted to disrupt individual effector pathways. Indeed, we have defined an Arl13b point mutation that
disrupts the role of Arl13b in ciliogenesis but leaves the Shh response intact, indicating that the processes can
be genetically uncoupled. In the next five years, using ARL13B mutants, a series of cell-based assays, and cell
lines in which we can circumvent ciliogenesis or sensitize Hh disruption, we plan to unravel Arl13b function in
ciliogenesis, cilia maintenance, traffic of proteins to/within cilia, and Shh signal transduction at unprecedented
resolution. We expect Arl13b mutants will provide a genetic entry point from which we will identify at least a
subset of effector proteins and define their mechanisms of action. The work in cell culture will enable us to
select specific ARL13B mutants for which we can generate mouse models and bring our work full circle back to
in vivo phenotypic characterization. In addition, we are integrating the novel alleles we discovered into our
analysis. Thus, our proposal will generate a molecular genetic toolkit from which the field will be poised to
distinguish the regulation of cilia from that of Hh signaling. This is important to our fundamental understanding
of cilia, ciliogenesis, and cilia structure, as well as our basic comprehension of the Shh pathway.

## Key facts

- **NIH application ID:** 10244952
- **Project number:** 5R35GM122549-05
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** TAMARA J. CASPARY
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $388,058
- **Award type:** 5
- **Project period:** 2017-09-20 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10244952

## Citation

> US National Institutes of Health, RePORTER application 10244952, Genetic Dissection of Signaling and Cilia (5R35GM122549-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10244952. Licensed CC0.

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