# Regulation of Cranial Mesenchyme Expansion Driving Neural Fold Elevation

> **NIH NIH R01** · CHILDREN'S RESEARCH INSTITUTE · 2020 · $383,775

## Abstract

Project Summary/Abstract
Neural tube defects (NTDs) are among the most common structural birth defects in humans and result in long-
term disability or even death; yet, the underlying genetic causes remain largely unknown. Addressing this gap in
knowledge is best achieved in the context of understanding the mechanisms mediating both normal and
abnormal development. Experiments conducted nearly 40 years ago indicate that expansion of the cranial
mesenchyme, a cell population that resides beneath the neural plate, is required for elevation of the cranial
neural folds and neural tube closure. Yet, little is known regarding how expansion of the cranial mesenchyme
drives neural fold elevation and how this process can be disrupted to cause NTDs. Moreover, few genes have
been implicated in this process.
In this proposal we present a novel mouse model of NTDs with a mutation in the Hectd1 gene and describe
approaches that will significantly advance our understanding of how cranial mesenchyme expansion can be
disrupted contributing to NTDs. Based on our previous and preliminary data we hypothesize that eHSP90
secreted from Hectd1 mutant NC-CM stimulates increase movement of the CM interfering with expansion
of the PM-CM and disrupting neural fold elevation (Specific Aims 1 & 2). We further hypothesize that
HECTD1 sequence variants associated with human NTDs employ the same pathogenic mechanism
(Specific Aim 3). We will test these hypotheses using a combination of innovative tools including: (1) advanced
imaging approaches to visualize, at unprecedented resolution expansion of the cranial mesenchyme in real time
during neural fold elevation, (2) fluorescently labeled eHSP90 probes to elucidate spatial and temporal patterns
of pathogenic eHSP90 production, (3) an ex vivo cranial mesenchyme explant assay amenable to experimental
manipulation, (4) a novel allelic series of mouse lines and (5) pharmacological inhibitors to test whether eHSP90
mediates failure of cranial mesenchyme expansion and neural fold elevation in Hectd1 mutant embryos. These
innovative tools will be combined with well-established conditional genetic, histological and embryological
approaches to delineate, in unprecedented detail, expansion of cranial mesenchyme in normal neural fold
elevation and how this process goes awry during failed cranial mesenchyme expansion responsible for NTDs in
the Hectd1 mutant embryo. This information will be used to determine the impact of predicted pathogenic
sequence variants of HECTD1 identified in human NTD cases and ascertain if variants disrupt HECTD1 function
and contribute to NTDs in human patients.

## Key facts

- **NIH application ID:** 9893986
- **Project number:** 1R01HD098861-01A1
- **Recipient organization:** CHILDREN'S RESEARCH INSTITUTE
- **Principal Investigator:** Irene E Zohn
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $383,775
- **Award type:** 1
- **Project period:** 2020-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9893986

## Citation

> US National Institutes of Health, RePORTER application 9893986, Regulation of Cranial Mesenchyme Expansion Driving Neural Fold Elevation (1R01HD098861-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9893986. Licensed CC0.

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