Cleft palate represents one of the major groups of 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. Cranial neural crest (CNC) is an important population of multipotent embryonic progenitor cells which ultimately contribute to a diverse array of differentiated craniofacial tissues, including the palatal mesenchyme, and plays an integral role during palatogenesis. An understanding of the manner in which CNC cells contribute to palatal development and the molecular mechanism which regulates the fate of CNC are critical for understanding normal craniofacial development as well as CNC-related congenital malformations. Multiple growth and transcription factors have been identified as critical regulators for palatogenesis. Specifically, TGF-[3 plays a pivotal role in regulating the fate of medial edge epithelium during palatal fusion. It is not well understood, however, what is the functional significance of TGF-]3 signaling in regulating the fate of CNC- derived palatal mesenchyme. To address this issue, we have generated an animal model with conditional TGF-13 type 1I receptor (TGF-fl IIli?_;Wntl-Cre) gene ablation in neural crest cells. These TGF-fl IIR_;Wntl-Cre mice show cleft palate and other craniofacial defects with 100% phenotype penetrance. Significantly, there is normal CNC migration into the first branchial arch of TGF-fl IIRJT_;Wntl-Cre embryos, indicating that disruption of TGF-[5 signaling does not adversely affect CNC migration. Therefore, TGF-J3-mediated gene expression is specifically required locally during palatal development. Taking advantage of our TGF-fl IIR_N, ?Wntl-Cre and other mutant animal models we design studies to investigate the hierarchy of TGF-13 signaling in regulating the fate of CNC cells during palatogenesis by testing the hypothesis that TGF-[3 signaling regulates the expression of homeobox gene Msxl, which in turn controls the progression of cell cycle to regulate the fate of CNC-derived palatal mesenchymal cells during palatogenesis. Ultimately, this study will provide a better understanding on how the TGF-[3 signaling cascade regulates the fate of CNC cells during normal craniofacial development and how signaling disruption can lead to craniofacial malformations.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
3R01DE012711-09S1
Application #
7490871
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Scholnick, Steven
Project Start
1999-01-01
Project End
2009-03-31
Budget Start
2007-09-01
Budget End
2009-03-31
Support Year
9
Fiscal Year
2007
Total Cost
$1,190,074
Indirect Cost
Name
University of Southern California
Department
Dentistry
Type
Schools of Dentistry
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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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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