# Mechanisms of Abnormal Cranial Mesenchyme Morphogenesis in the Hectd1 mutant

> **NIH NIH F31** · CHILDREN'S RESEARCH INSTITUTE · 2023 · $44,389

## Abstract

PROJECT SUMMARY
While the cellular movements and shape changes that drive morphogenesis within the neural plate are well
characterized, how morphogenesis of different cranial mesenchyme (CM) lineages contributes to neural fold
elevation and how disruption of these mechanisms results in neural tube defects remains an open question.
This application is based on the hypothesis that aberrant eHSP90 secretion and changes in the CM
matrisome result in abnormal CM behavior, disrupting CM expansion in the Hectd1 mutant embryo. To
model abnormal CM morphogenesis, a Hectd1 mouse mutant that fails neural tube closure will be used to
determine both lineage relationship and gene expression changes that occur with CM morphogenesis leading
to the neural tube defect.
 Aim 1 will assess how the neural crest (NC-CM) and paraxial mesoderm derived CM (PM-CM) interact in
the Hectd1 mutant embryo leading to abnormal CM morphogenesis and failure of neural fold elevation. Both
CM lineages are implicated as critical mediators of neural fold elevation. Analysis using SiMView adaptive light
sheet microscope during normal CM expansion demonstrated distinct movements of the PM-CM and the NC-
CM. Secondly, preliminary analysis of CM cells indicates that NC-CM cells are the primary migratory cells.
Hectd1 is required in the NC-CM for neural fold elevation, but the PM-CM also fails to expand in the Hectd1
mutant. Therefore, lineage tracing and conditional genetic models of Hectd1 will be used to test the
contribution of the NC-CM and PM-CM to abnormal morphogenesis in the Hectd1 mutant line using live
imaging of in vitro CM explant assays. Lastly, increased extracellular HSP90 (eHSP90) secretion is observed
in NC-CM cells of our mutant mouse. This potential mechanism for their abnormal interaction leading to the
neural tube defect will be tested with additional live imaging of CM explants with the addition of eHSP90.
 Aim 2 will assess the changes in matrisome gene expression of the CM during neural fold elevation. The CM
cells are embedded in an extracellular matrix (ECM), which undergoes expansion during neural fold elevation.
The ECM is critical to morphogenesis in many systems. Embryonic tissues from key timepoints will be
analyzed using bulk RNA sequencing to identify extracellular matrix genes implicated in CM morphogenesis in
neural fold elevation. Bioinformatics analyses will identify differentially expressed genes, and in situ
hybridization experiments will map critical differential gene expression across different time points. Successful
completion of these studies will transform our understanding of the mechanisms leading to neural tube defects
and address a crucial gap in our understanding of neural tube formation.

## Key facts

- **NIH application ID:** 10686499
- **Project number:** 1F31HD112200-01
- **Recipient organization:** CHILDREN'S RESEARCH INSTITUTE
- **Principal Investigator:** Claire Marie Moran
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $44,389
- **Award type:** 1
- **Project period:** 2023-03-15 → 2025-03-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10686499

## Citation

> US National Institutes of Health, RePORTER application 10686499, Mechanisms of Abnormal Cranial Mesenchyme Morphogenesis in the Hectd1 mutant (1F31HD112200-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10686499. Licensed CC0.

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