# Mechanisms of folate action during nervous system development

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2021 · $343,438

## Abstract

Project summary
Neural tube defects (NTDs) are among the most common serious birth defects diagnosed in human fetuses and
newborns with a combined incidence of ~1/1,000 in the United States and an estimated of 300,000 or more
newborns worldwide each year. NTDs result from the failure of neural tube closure during the early fetal
development. A combination of genetic and environmental factors appears to regulate the formation of the neural
tube. Notably, folate supplementation during pregnancy prevents NTDs by unclear mechanisms. Our recently
published study demonstrates that folate receptor 1 (Folr1), one of folate uptake systems, localizes to the apical
surface of Xenopus laevis neural plate and is necessary for neural plate cell apical constriction during neural
plate folding. Moreover, we find that Folr1 interacts with adherens junction components, C-cadherin and β-
catenin suggesting that folate signaling might regulate neural plate cell-cell adhesion during neural tube
formation. Our overall research goal is to elucidate the cellular and molecular mechanisms underlying neural
tube formation. We will test the hypothesis that folate participates in the changes in cell shape that neural cells
undergo during neurulation by recruiting its receptor and triggering a novel and dynamic signaling pathway. The
first specific aim will consist in determining the molecular mechanisms underlying folate/Folr1 promotion of neural
plate cell apical constriction during neural tube formation. We will identify the molecular mechanisms of Folr1
regulation of cell adhesion remodeling necessary for neural tube formation. In the second specific aim we will
discover the signaling pathways recruited by folate/Folr1 that are necessary for neural plate cell apical
constriction and neural tube formation. We will interrogate the ubiquitination pathway through gain and loss of
function approaches and epistasis experiments. We will assess the role of folate in cell adhesion molecule and
cytoskeletal dynamics by live imaging embryos expressing fluorescently tagged proteins or reporters of cell
adhesion and cytoskeletal components during neural tube formation. We will use state-of-the-art methodologies
including proteomics of immunoprecipitates, super resolution microscopy, reporters of cytoskeletal and cell
adhesion dynamics and optogenetic approaches to manipulate signaling pathways. Although folate fortification
has been a highly effective public health measure in reducing NTDs, the lack of mechanism-based understanding
of NTD prevention leads to general concerns regarding unintended consequences resulting from
supplementation. Optimal folate supplementation, risk groups and treatment of folate-insensitive NTDs are some
of the unsolved clinical aspects awaiting for the full elucidation of the molecular and cellular mechanisms
underlying folate action in neural tube formation.

## Key facts

- **NIH application ID:** 10115144
- **Project number:** 5R01NS105886-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Laura Noemi Borodinsky
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $343,438
- **Award type:** 5
- **Project period:** 2019-05-15 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10115144

## Citation

> US National Institutes of Health, RePORTER application 10115144, Mechanisms of folate action during nervous system development (5R01NS105886-03). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10115144. Licensed CC0.

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