# Role of cellular metabolism in palate morphogenesis

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2022 · $366,795

## Abstract

Project Abstract
Cleft palate is one of the most common congenital birth defects, with a prevalence of 1/700 live births worldwide.
Human linkage studies have shown that either genetic mutations related to cholesterol metabolism or abnormal
maternal cholesterol diets lead to craniofacial deformities such as cleft palate. However, it is largely unknown
how disturbances in cholesterol production result in cleft palate. In our preliminary studies, we found that mice
with loss of sterol-C5-desaturase (Sc5d) displayed cleft palate with complete penetrance through decreased cell
proliferation during palate formation. Sonic hedgehog (SHH) signaling, which is crucial for normal palate
formation, was compromised in Sc5d mutant mice. The primary cilium, an antenna-like structure receiving
hedgehog signals on the plasma membrane, was deformed in palatal mesenchymal cells of Sc5d mutant mice.
We also found that posttranscriptional protein modification and expression of non-coding RNAs was altered in
the palate of Sc5d mutant mice. Interestingly, while cholesterol synthesis is inhibited similarly in mice deficient
for the 7-dehydrocholesterol reductase (Dhcr7) gene, which is crucial for cholesterol synthesis right after SC5D,
these mice display cleft palate with a penetrance lower than 10%. Based on this foundation, in this project we
will test the hypothesis that lathosterol, a cholesterol precursor that is elevated in Sc5d mutant mice, plays crucial
roles in the pathogenesis of cleft palate. We have three specific aims; (1) To determine how a specific cholesterol
intermediate interferes with SHH signaling by testing how lathosterol, a cholesterol intermediate accumulated in
Sc5d mutant mice, interferes with hedgehog receptor movement and primary cilium formation; (2) To identify
altered proteins and modifications in the developing palate of Sc5d mutant mice by conducting proteomic
analyses using the palate of Sc5d mutant, Dhcr7 mutant, and control mice; (3) To identify non-coding RNAs and
their regulated genes influenced by impaired cholesterol metabolism through analysis of the regulatory
mechanism(s) of microRNAs (short non-coding RNAs) and their regulation of genes associated with cleft palate
that are specifically altered in Sc5d mutant mice. Building on our strong preliminary work, we expect this study
will systematically investigate the roles of cholesterol metabolism (at the cellular, metabolic, proteomic, and post-
transcriptional regulation levels) in cleft palate in mice, and the results will lead to innovations in the prevention,
diagnosis, and treatment of cholesterol-related craniofacial birth defects.

## Key facts

- **NIH application ID:** 10398249
- **Project number:** 5R01DE029818-03
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Junichi Iwata
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $366,795
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10398249

## Citation

> US National Institutes of Health, RePORTER application 10398249, Role of cellular metabolism in palate morphogenesis (5R01DE029818-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10398249. Licensed CC0.

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