# TGF BETA SIGNALING AND CRANIOFACIAL MORPHOGENESIS

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2020 · $391,875

## Abstract

PROJECT SUMMARY / ABSTRACT
Cleft palate represents one of the most common congenital birth defects in the human population. Despite
recent advancements in medical intervention, babies born with cleft palate often suffer multiple handicaps that
significantly compromise the quality of their lives. The causes of cleft palate are numerous, including multiple
genetic and environmental factors (Chai and Maxson, 2006; Dixon et al., 2011). Recent studies have identified
a large number of signaling pathways that regulate hard palate development. However, the regulatory
mechanisms for development of the soft palate are largely unknown. The soft palate in humans consists of five
muscles that are functionally highly active in our daily lives as they form a critical component of our
oropharyngeal complex. Cleft of the soft palate leads to misorientation of these muscles, causing
oropharyngeal deficiency and adversely affecting speech, swallowing, breathing and hearing. Our preliminary
studies have shown that TGF- signaling is specifically required in cranial neural crest-derived cells (CNCCs)
for regulating tissue-tissue interactions to control soft palate development. Furthermore, we have uncovered
important TGF- downstream target genes, such as Dlx5 and Runx2, which may play crucial roles in regulating
soft palate development. Our preliminary data show that Runx2 is specifically required for regulating CNCC
and myogenic progenitor interaction during soft palate development. Loss of Runx2 in CNCCs leads to cleft of
the soft palate. Based on this foundation, we will test the hypothesis that TGF- regulates the expression of
key transcription factors, such as Dlx5 and Runx2, which function to mediate CNC and myogenic cell
interaction to control the patterning and development of muscles in the soft palate. Our Specific Aims are: (1)
To investigate how Alk5-mediated TGF- signaling in CNCCs controls muscle patterning and development
through tissue-tissue interactions. We will analyze the molecular and cellular defects in the soft palate of Alk5
mutant mice. We will test how TGF-downstream signaling molecules play key roles in regulating cell-cell
interactions using an organ-on-a-chip model and explore the potential to rescue the myogenic defect in the soft
palate of Alk5 mutant mice. (2) To investigate the functional significance of Dlx5 signaling in CNCCs in
regulating the fate of myogenic progenitors during soft palate muscle development. We will test how Wnt
signaling and chromatin remodeler Arid1a, acting downstream of Dlx5, may play a key role in mediating tissue-
tissue interaction to control soft palate muscle development. (3) To investigate how Runx2, acting downstream
of Alk5-mediated TGF- signaling, may exert its regulatory role in controlling tissue-tissue interactions to
regulate soft palate development. We will also test whether Dlx5/Runx2 interaction may play a key role in
regulating soft palate development.

## Key facts

- **NIH application ID:** 9978029
- **Project number:** 5R01DE012711-22
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Yang Chai
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $391,875
- **Award type:** 5
- **Project period:** 1999-01-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9978029

## Citation

> US National Institutes of Health, RePORTER application 9978029, TGF BETA SIGNALING AND CRANIOFACIAL MORPHOGENESIS (5R01DE012711-22). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9978029. Licensed CC0.

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