# Folate-directed signaling in C. elegans

> **NIH NIH R01** · UNIVERSITY OF GEORGIA · 2022 · $302,000

## Abstract

Project Summary
The folate receptor is one of three major types of folate transporters. The human folate receptor is
required for proper neural tube development, and is often overexpressed in cancers where it
contributes to cancer progression. In both of these processes, there is emerging evidence that the
foIate receptor acts independently of providing folates as vitamins for one-carbon metabolism. The
small roundworm C. elegans obtains folates from its food source of bacteria. We have discovered
that a specific bacterial folate (10-formyl-THF) increases the rate of proliferation of C. elegans germ
stem cells, thereby acting as a signal to link the rate of proliferation to the availability of the animal’s
bacterial diet. Additionally, we discovered that 10-formyl-THF acts as a signal to activate the NSM
neurons. The activation of the NSM neurons causes starved animals to stop their forward motion
when they encounter bacteria. Both of these processes require the C. elegans folate receptor,
FOLR-1, and are independent of providing folates for their canonical role in one-carbon metabolism.
The goal of this proposal is to identify the molecular pathways through which FOLR-1 mediates
signals from the stimulatory folate to germ cells and the NSM neurons. We will use fluorescent tags
to determine where FOLR-1 is localized in cells and whether the localization changes in the presence
of stimulatory folates. Genetic experiments suggest that FOLR-1 functions in both neuronal and non-
neuronal tissues to mediate the activation of the NSM neuron. We discovered that the GON-2
calcium channel is required for the calcium influx that accompanies NSM neuronal activation. Similar
to FOLR-1, GON-2 is also required in both neuronal and non-neuronal tissues for NSM activation.
Using genetic approaches, we will identify the tissues in which FOLR-1 and GON-2 each function to
allow NSM activation. We discovered that GON-2 is also required both to maintain calcium levels in
the germline and for normal germ cell proliferation, suggesting that increased calcium levels promote
germ cell proliferation. We will determine if calcium levels differ in response to growth conditions and
stimulatory folate, and the role of GON-2 and FOLR-1 in altering calcium levels. Genetic approaches
will be used to identify the downstream effectors that alter germ cell proliferation in response to
altered calcium levels in the germline. Unbiased genetic screens will be used to identify components
and regulators of the stimulatory-folate pathway(s). The identified genes will be analyzed using
genetic and biochemical approaches to determine how they contribute to the pathway(s). This
research will uncover the molecular pathway(s) through which folates regulate diverse cellular
processes independently of their role in metabolism. This will provide a paradigm for understanding
non-canonical folate pathways, with the potential for insights into neural tube defects and cancer.

## Key facts

- **NIH application ID:** 10348183
- **Project number:** 5R01GM134359-03
- **Recipient organization:** UNIVERSITY OF GEORGIA
- **Principal Investigator:** EDWARD T. KIPREOS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $302,000
- **Award type:** 5
- **Project period:** 2020-04-15 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10348183

## Citation

> US National Institutes of Health, RePORTER application 10348183, Folate-directed signaling in C. elegans (5R01GM134359-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10348183. Licensed CC0.

---

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