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-beta 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-beta signaling in regulating the fate of CNC derived palatal mesenchyme. To address this issue, we have generated an animal model with conditional TGF-beta type II receptor (TGF-beta IIRfl/fl;Wnt1-Cre) gene ablation in neural crest cells. These TGF-beta IIRfl/fl;Wnt1-Cre mice show cleft palate and other craniofacial defects with 100 percent phenotype penetrance. Significantly, there is normal CNC migration into the first branchial arch of TGF-beta IIRfl/fl;Wnt1-Cre embryos, indicating that disruption of TGF-( signaling does not adversely affect CNC migration. Therefore, TGF-beta-mediated gene expression is specifically required locally during palatal development. Taking advantage of our TGF-beta IIRfl/fl;Wnt1-Cre and other mutant animal models we design studies to investigate the hierarchy of TGF-beta signaling in regulating the fate of CNC cells during palatogenesis by testing the hypothesis that TGF-beta signaling regulates the expression of homeobox gene Msx1, 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-beta 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 #
3R01DE012711-10S1
Application #
7840747
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Scholnick, Steven
Project Start
2009-06-02
Project End
2010-05-31
Budget Start
2009-06-02
Budget End
2010-05-31
Support Year
10
Fiscal Year
2009
Total Cost
$13,692
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
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; Parada, Carolina; Chai, Yang (2017) Cellular and molecular mechanisms of tooth root development. Development 144:374-384
Feng, Jifan; Jing, Junjun; Sanchez-Lara, Pedro A et al. (2016) Generation and characterization of tamoxifen-inducible Pax9-CreER knock-in mice using CrispR/Cas9. Genesis 54:490-6
Parada, Carolina; Han, Dong; Grimaldi, Alexandre et al. (2015) Disruption of the ERK/MAPK pathway in neural crest cells as a potential cause of Pierre Robin sequence. Development 142:3734-45
Zhao, Hu; Feng, Jifan; Ho, Thach-Vu et al. (2015) The suture provides a niche for mesenchymal stem cells of craniofacial bones. Nat Cell Biol 17:386-96
Ho, Thach-Vu; Iwata, Junichi; Ho, Hoang Anh et al. (2015) Integration of comprehensive 3D microCT and signaling analysis reveals differential regulatory mechanisms of craniofacial bone development. Dev Biol 400:180-90
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
Iwata, Junichi; Suzuki, Akiko; Pelikan, Richard C et al. (2014) Modulation of lipid metabolic defects rescues cleft palate in Tgfbr2 mutant mice. Hum Mol Genet 23:182-93

Showing the most recent 10 out of 41 publications