The tongue is an important muscular organ and carries out crucial physiological functions. Despite the important functions of the tongue in our daily life, we know very little about the regulatory mechanism of mammalian tongue muscle development. The long term goal of this project is to understand the molecular and cellular mechanisms that control tissue-tissue interactions during tongue myogenesis. Specifically, our preliminary studies show that cranial neural crest (CNC) cells contribute to the interstitial connective tissue, which ultimately compartmentalizes both intrinsic and extrinsic tongue muscles and serves as their attachments. Occipital somite-derived cells migrate into tongue primordium and give rise to muscle cells in the tongue. The intimate relationship between CNC- and mesoderm-derived cells suggests that tissue-tissue interaction may play an important role in regulating tongue development. Transforming growth factor-? (TGF- ?) and its signaling mediator Smad are expressed in both CNC- and mesoderm-derived cells in the tongue. Significantly, disruption of TGF-? signaling in either CNC or mesoderm-derived cells does not adversely affect cell migration into the tongue primordium, indicating that TGF-? signaling is specifically required locally during tongue morphogenesis. We discovered that mutation of Tgfbr? in CNC cells results in a defect in tongue muscle patterning and microglossia, whereas loss of Tgfbr? in mesoderm-derived cells results in a myogenic differentiation defect with 100% phenotype penetrance. Taking advantage of our neural crest- or mesoderm- specific Tgfbr2 mutant animal models, we designed studies to test the hypothesis that TGF-? signaling controls the fate of CNC as well as mesoderm-derived cells and regulates tissue-tissue interaction during tongue development. Ultimately, this study will provide a better understanding of how the TGF-? signaling cascade regulates the fate of the CNC- and mesoderm derived cells during normal craniofacial development and how signaling pathway disruption can lead to craniofacial malformations. This study will have a broad impact on our understanding of the regulatory mechanism of skeletal muscle development and regeneration.

Public Health Relevance

The tongue is a muscular organ and plays a critical role in speech, deglutition, and taste. Tongue development defects severely affect the physiological function of the tongue. Despite these important functions of the tongue, we know very little about the control of tongue development. This research program is designed to obtain important information in order to have a clear understanding how different gene mutations adversely affect tissue-tissue interactions during tongue development and lead to tongue malformation. Ultimately, this investigation will provide important information on future prevention and treatment of skeletal muscle defects.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE014078-10
Application #
8474630
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Scholnick, Steven
Project Start
2001-04-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
10
Fiscal Year
2013
Total Cost
$362,010
Indirect Cost
$138,547
Name
University of Southern California
Department
Dentistry
Type
Schools of Dentistry
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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
Mima, Junko; Koshino, Aya; Oka, Kyoko et al. (2013) Regulation of the epithelial adhesion molecule CEACAM1 is important for palate formation. PLoS One 8:e61653
Iwata, Jun-ichi; Suzuki, Akiko; Pelikan, Richard C et al. (2013) Noncanonical transforming growth factor * (TGF*) signaling in cranial neural crest cells causes tongue muscle developmental defects. J Biol Chem 288:29760-70
Pelikan, Richard C; Iwata, Junichi; Suzuki, Akiko et al. (2013) Identification of candidate downstream targets of TGFýý signaling during palate development by genome-wide transcript profiling. J Cell Biochem 114:796-807
Song, Zhongchen; Liu, Chao; Iwata, Junichi et al. (2013) Mice with Tak1 deficiency in neural crest lineage exhibit cleft palate associated with abnormal tongue development. J Biol Chem 288:10440-50
Iwata, Jun-ichi; Tung, Lily; Urata, Mark et al. (2012) Fibroblast growth factor 9 (FGF9)-pituitary homeobox 2 (PITX2) pathway mediates transforming growth factor ýý (TGFýý) signaling to regulate cell proliferation in palatal mesenchyme during mouse palatogenesis. J Biol Chem 287:2353-63
Han, Dong; Zhao, Hu; Parada, Carolina et al. (2012) A TGF*-Smad4-Fgf6 signaling cascade controls myogenic differentiation and myoblast fusion during tongue development. Development 139:1640-50
Parada, C; Han, D; Chai, Y (2012) Molecular and cellular regulatory mechanisms of tongue myogenesis. J Dent Res 91:528-35
Zhao, Hu; Li, Sha; Han, Dong et al. (2011) Alk5-mediated transforming growth factor ýý signaling acts upstream of fibroblast growth factor 10 to regulate the proliferation and maintenance of dental epithelial stem cells. Mol Cell Biol 31:2079-89
Huang, X; Yokota, T; Iwata, J et al. (2011) Tgf-beta-mediated FasL-Fas-Caspase pathway is crucial during palatogenesis. J Dent Res 90:981-7

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