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.

Public Health Relevance

Cleft palate represents one of the most common congenital defects in the human population. Despite recent advancement in our understanding of the regulatory mechanism of hard palate development, we have limited knowledge on the regulatory mechanisms for development of the soft palate and have designed our current study to investigate how cell-cell interactions control muscle development in the soft palate. The knowledge gained from this study will serve as the foundation for the development of new approaches to soft palate muscle repair and regeneration.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE012711-22
Application #
9978029
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Stein, Kathryn K
Project Start
1999-01-01
Project End
2024-07-31
Budget Start
2020-08-01
Budget End
2021-07-31
Support Year
22
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Southern California
Department
Dentistry
Type
Schools of Dentistry/Oral Hygn
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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Iwata, Jun-ichi; Suzuki, Akiko; Yokota, Toshiaki et al. (2014) TGF? regulates epithelial-mesenchymal interactions through WNT signaling activity to control muscle development in the soft palate. Development 141:909-17
Han, Arum; Zhao, Hu; Li, Jingyuan et al. (2014) ALK5-mediated transforming growth factor ? signaling in neural crest cells controls craniofacial muscle development via tissue-tissue interactions. Mol Cell Biol 34:3120-31
Zhao, Hu; Feng, Jifan; Seidel, Kerstin et al. (2014) Secretion of shh by a neurovascular bundle niche supports mesenchymal stem cell homeostasis in the adult mouse incisor. Cell Stem Cell 14:160-73

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