# Project III - Modeling meningomyelocele alleles and response to folic acid diet in mouse

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $254,393

## Abstract

Abstract – Project III Modeling meningomyelocele alleles and response to folic acid diet in mouse
The overall hypothesis of the Program Project grant is that de novo mutations contribute to meningomyelocele
(MM) risk and that folic acid (FA) influences the genome through chromatin accessibility and modulation of gene
expression, to alter this risk. The mouse is considered the gold standard model for human neural tube defects
(NTDs), because development is highly conserved in mammals, leading to similar types of cranial and caudal
NTDs, utilizing similar genes, and responding to similar environmental factors. The mouse has been invaluable
in defining genes required for neural tube closure, now numbering over 250 genes, and highlighting the need for
exquisite precision of cell proliferation, actin regulation, planar cell polarity/WNT signaling, cilia/Hedgehog
signaling, and FA metabolism. Many mouse NTD models show allele-specific effects, where for example,
homozygous null mice are embryonic lethal, heterozygous null mice are healthy, but specific point mutations,
some heterozygous, some homozygous, show NTD. In many of these mouse models, NTDs often occur in less
than 100% of offspring, even in an entirely pure genetic background, reflecting background-independent partial
penetrance. Like in human, the penetrance and expressivity of NTD phenotypes can be influenced by FA
exposure, with about half of genes tested to date showing FA responsiveness. FA has been supplemented in
grains in the US diet since 1998, regulating biosynthesis of nucleotides and S-adenosylmethionine, the universal
methyl donor for DNA methylation. To account for these observations, we hypothesize that NTD risk is
established by mutations in a core set of genes, with risk modified by FA-dependent changes in the
epigenome. Project III has already assembled the following preliminary data: 1] Performed recessive ENU-
mutagenesis screens for genes essential for neural tube closure. 2] Assembled a growing collection of genes
and alleles from more than 30 NTD mutants. 3] Demonstrated mutations in primary ciliary genes underlying
several mouse NTD mutants. 4] Demonstrated an impact of FA on penetrance and expressivity of murine NTDs.
5] Developed live-cell imaging platform to observe mammalian neural tube closure in real-time. 6] Modeled
meningomyelocele in mouse for the human MM gene WLS. This proposal focuses on evaluating genes and
alleles emerging from Project I and II as risk factors for MM, as well as the FA-dependent changes in the
methylome and transcriptome that can influence this risk. Altogether, the goal of Project III is to define the
relationships and interplay between mammalian MM mutations and FA influences on penetrance and
expressivity.
Aim 1. Model human meningomyelocele (MM) variants and genetic interactions to assess expressivity.
Aim 2. Assess impact of folic acid on NTD expressivity on a gene-by-gene basis.
Aim 3. Assess impact of folic acid on the neural tube ...

## Key facts

- **NIH application ID:** 10154467
- **Project number:** 1P01HD104436-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Lee A. Niswander
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $254,393
- **Award type:** 1
- **Project period:** 2020-12-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10154467

## Citation

> US National Institutes of Health, RePORTER application 10154467, Project III - Modeling meningomyelocele alleles and response to folic acid diet in mouse (1P01HD104436-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10154467. Licensed CC0.

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