The long term goal of this research project is to understand the molecular regulatory mechanism of TGF-? signaling during palatogenesis. Cleft palate represents one of the major groups of congenital birth defects in the human population. Importantly, we and others have shown that mutations in TGF-? signaling can cause cleft palate in both mice and humans. Specifically, TGF-? is required for inducing apoptosis in the medial edge epithelium (MEE) and cell proliferation in the cranial neural crest (CNC)-derived palatal mesenchyme, both of which are crucial for normal palatal fusion. In this competing renewal application, we will carry out experiments to test the hypotheses that TGF-? signaling mediator Smad4, its downstream target Msx1 and the interaction between Smad4 and Msx1 are crucial for the cell fate determination of CNC-derived palatal mesenchyme. Furthermore, TGF-? regulates the expression of downstream target genes, such as Irf6 and Ctgf, to control the fate of MEE and CNC cells during palatogenesis. We have proposed three specific aims.
In Specific Aim 1, we will investigate the functional significance of Smad4 in regulating the fate of CNC- derived palatal mesenchyme during palatogenesis. Furthermore, we will test the hypotheses that there is a CNC cell-autonomous requirement for Msx1 signaling during palatogenesis and Smad4/Msx1 interaction is crucial for regulating the fate of CNC-derived palatal mesenchyme.
In Specific Aim 2, we will investigate the functional significance of TGF-? mediated Irf6 signaling in controlling the fate of MEE cells during palatal fusion. We will test the hypotheses that TGF-? is responsible for inducing Irf6 expression in MEE cells, Irf6 is required for MEE cells to undergo apoptosis, and TGF-?-mediated Irf6 expression is critical for apoptosis in MEE cells and for normal palatal fusion.
In Specific Aim 3, we will explore the biological significance of TGF-? signaling mediated Ctgf expression in regulating CNC cell proliferation during palatogenesis. We will test the hypotheses that TGF-?-induced Ctgf expression is required for CNC cell proliferation in the developing palatal shelf and TGF-?-mediated CTGF signaling is critical for palatogenesis. Ultimately, this study will provide a better understanding of how the TGF-? signaling cascade regulates palatogenesis and will lead to the development of methods for better diagnosis, treatment and prevention of cleft palate.

Public Health Relevance

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. Significantly, mutations in the Transforming Growth Factor-? (TGF-?) gene cause cleft palate in humans and mice. This research program is designed to further our understanding of how aberrant TGF-? signaling may adversely affect cell fate determination during palatogenesis and causes cleft palate. Ultimately, this investigation will provide important information for the future prevention and treatment of craniofacial birth defects.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Method to Extend Research in Time (MERIT) Award (R37)
Project #
Application #
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Scholnick, Steven
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Southern California
Schools of Dentistry
Los Angeles
United States
Zip Code
Zhao, Hu; Feng, Jifan; Seidel, Kerstin et al. (2018) Secretion of Shh by a Neurovascular Bundle Niche Supports Mesenchymal Stem Cell Homeostasis in the Adult Mouse Incisor. Cell Stem Cell 23:147
Li, Jingyuan; Yuan, Yuan; He, Jinzhi et al. (2018) Constitutive activation of hedgehog signaling adversely affects epithelial cell fate during palatal fusion. Dev Biol 441:191-203
Bobarnac Dogaru, Gabriela L; Juneja, Subhash C; Shokrani, Alireza et al. (2018) The role of Hedgehog-responsive fibroblasts in facial nerve regeneration. Exp Neurol 303:72-79
Tian, Hua; Feng, Jifan; Li, Jingyuan et al. (2017) Intraflagellar transport 88 (IFT88) is crucial for craniofacial development in mice and is a candidate gene for human cleft lip and palate. Hum Mol Genet 26:860-872
Li, Jingyuan; Parada, Carolina; Chai, Yang (2017) Cellular and molecular mechanisms of tooth root development. Development 144:374-384
Feng, Jifan; Jing, Junjun; Li, Jingyuan et al. (2017) BMP signaling orchestrates a transcriptional network to control the fate of mesenchymal stem cells in mice. Development 144:2560-2569
Sugii, Hideki; Grimaldi, Alexandre; Li, Jingyuan et al. (2017) The Dlx5-FGF10 signaling cascade controls cranial neural crest and myoblast interaction during oropharyngeal patterning and development. Development 144:4037-4045
Park, Shery; Zhao, Hu; Urata, Mark et al. (2016) Sutures Possess Strong Regenerative Capacity for Calvarial Bone Injury. Stem Cells Dev 25:1801-1807
Sun, Zhao; Yu, Wenjie; Sanz Navarro, Maria et al. (2016) Sox2 and Lef-1 interact with Pitx2 to regulate incisor development and stem cell renewal. Development 143:4115-4126
Burg, Madeleine L; Chai, Yang; Yao, Caroline A et al. (2016) Epidemiology, Etiology, and Treatment of Isolated Cleft Palate. Front Physiol 7:67

Showing the most recent 10 out of 52 publications