# Genetic analysis of nematode cell differentiation

> **NIH NIH R35** · COLUMBIA UNIV NEW YORK MORNINGSIDE · 2024 · $820,879

## Abstract

We will continue our study of genes needed for neuronal differentiation and
function using the six touch receptor neurons (TRNs) of the nematode Caenorhabditis
elegans. Our previous research identified genes needed for the generation,
specification, maintenance, and function of the TRNs. In the last grant period, we 1)
identified a “double negative” type of neuronal specification, where an inhibitory
transcription factor prevents the expression of a repressor transcription factor; 2)
analyzed the effects of tubulin mutations on neuronal outgrowth; 3) used the
suppression of mutations affecting a TRN-specific β-tubulin and a TRN-specific α-tubulin
acetyltransferase as sensitized backgrounds to identify other genes needed for neuronal
outgrowth, finding genes needed for protein degradation and gap-junction function; 4)
discovered a novel balancing system needed for proper neurite outgrowth in which the
protein degradation machinery is opposed by the HSP90 chaperone system; 5)
demonstrated the usefulness of the Million Mutation Project (MMP) strains, a collection
of completely sequence strains from the Waterston and Moerman labs, as a tool for
gene discovery and identified many new touch mutants; 6) investigated neuronal
ensheathment and discovered 14 new genes affecting it, including genes that are
important for mechanosensory ECM, adhesion complexes, axon guidance, and axonal
transport; and 7) discovered a synthetic ensheathment phenotype that we will exploit in
the future. The general goal of the research going forward is to exploit these findings to
understand how the differentiation of individual neurons is controlled and how
mechanical inputs are sensed and modified. The most important experiments for the
future are the elucidation of the molecular structure of the transduction complex using
cryo-EM and the discovery and analysis of genes whose loss causes an increase in
touch sensitivity, since these will be negative regulators of touch. We also intend to
continue analyzing the new touch genes uncovered by our work with the MMMP strains,
to revisit the analysis of an important cholesterol-binding component of the touch system
(MEC-2), to exploit the discovery of a synthetic genetic relationship affecting TRN
ensheathment to discover and characterize additional genes needed for this process.
The health relatedness of our work comes from the discovery of new genes and new
interactions among genes that are similar in humans and other mammals.

## Key facts

- **NIH application ID:** 10825500
- **Project number:** 5R35GM122522-07
- **Recipient organization:** COLUMBIA UNIV NEW YORK MORNINGSIDE
- **Principal Investigator:** MARTIN CHALFIE
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $820,879
- **Award type:** 5
- **Project period:** 2017-04-14 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10825500

## Citation

> US National Institutes of Health, RePORTER application 10825500, Genetic analysis of nematode cell differentiation (5R35GM122522-07). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10825500. Licensed CC0.

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