The fibroblast growth factors (FGFs) and the fibroblast growth factor receptors (FGFRs) play important roles in development, including skeletal and craniofacial development. Activating mutations in human FGFR1, FGFR2, and FGFRS are associated with skeletal dysplasias including craniosynostosis and dwarfing syndromes. These mutations affect the proliferation and differentiation of osteoblasts and chondrocytes. These data indicate a pivotal role for FGFR signaling in skeletal development: signaling by FGFRs must be tightly regulated for normal development. Important unresolved issues are the identification of pathways activated by FGFRs during skeletal development, and how these pathways feedback to regulate FGF signaling. Studies in Drosophila and vertebrates have demonstrated that members of the Sprouty (Spry) gene family are inhibitors of FGFR signaling. Spryl, Spry2, and Spry4 are expressed in the limb buds, and maxillary and mandibular arches, as well as other sites during mouse development. Retroviral-mediated over-expression of Spryl in chick limb buds results in chondrodysplasia. We have developed a conditional transgenic mouse model to explore the role of Spry family members in skeletal development. We show that conditional expression of Spryl in cranial neural crest cells results in severe craniofacial defects including the absence of the nasal and frontal bones. These mice also exhibit greatly reduced expression of the transcription factors Msx1, Msx2, and AP2 in craniofacial primordia. We hypothesize that the function of Spry in skeletal development is to maintain a balance between FGF- mediated proliferation, differentiation, and apoptosis, and that the level of Spry expression determines this balance. Accordingly, we propose the following three specific aims: 1) to test the hypothesis that over- expression of Spry inhibits FGF activity in bone primordia, leading to decreased overall osteoblast development;2) to use loss-of-function approaches to investigate the role of Spry in osteoblast proliferation, differentiation, and apoptosis in vivo;and 3) to characterize the mechanisms by which Spry affects osteoblast proliferation, differentiation, and apoptosis using calvarial cultures in vitro. These studies will provide significant insight into the negative regulation of signaling pathways in craniofacial and skeletal development and how perturbations in this feedback signaling pathway lead to skeletal dysplasias.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK073871-03
Application #
7535588
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Sato, Sheryl M
Project Start
2007-01-01
Project End
2011-11-30
Budget Start
2008-12-01
Budget End
2009-11-30
Support Year
3
Fiscal Year
2009
Total Cost
$357,551
Indirect Cost
Name
Maine Medical Center
Department
Type
DUNS #
071732663
City
Portland
State
ME
Country
United States
Zip Code
04102
He, Qing; Yang, Xuehui; Gong, Yan et al. (2014) Deficiency of Sef is associated with increased postnatal cortical bone mass by regulating Runx2 activity. J Bone Miner Res 29:1217-31
Urs, Sumithra; Henderson, Terry; Le, Phuong et al. (2012) Tissue-specific expression of Sprouty1 in mice protects against high-fat diet-induced fat accumulation, bone loss and metabolic dysfunction. Br J Nutr 108:1025-33
Franco, Hector L; Casasnovas, Jose J; Leon, Ruth G et al. (2011) Nonsense mutations of the bHLH transcription factor TWIST2 found in Setleis Syndrome patients cause dysregulation of periostin. Int J Biochem Cell Biol 43:1523-31
Yang, Xuehui; Kilgallen, Sean; Andreeva, Viktoria et al. (2010) Conditional expression of Spry1 in neural crest causes craniofacial and cardiac defects. BMC Dev Biol 10:48
Urs, Sumithra; Venkatesh, Deepak; Tang, Yuefeng et al. (2010) Sprouty1 is a critical regulatory switch of mesenchymal stem cell lineage allocation. FASEB J 24:3264-73
Chen, Pei-Yu; Friesel, Robert (2009) FGFR1 forms an FRS2-dependent complex with mTOR to regulate smooth muscle marker gene expression. Biochem Biophys Res Commun 382:424-9
Chen, Pei-Yu; Simons, Michael; Friesel, Robert (2009) FRS2 via fibroblast growth factor receptor 1 is required for platelet-derived growth factor receptor beta-mediated regulation of vascular smooth muscle marker gene expression. J Biol Chem 284:15980-92
Korc, M; Friesel, R E (2009) The role of fibroblast growth factors in tumor growth. Curr Cancer Drug Targets 9:639-51
Yang, Xuehui; Harkins, Lauren K; Zubanova, Olga et al. (2008) Overexpression of Spry1 in chondrocytes causes attenuated FGFR ubiquitination and sustained ERK activation resulting in chondrodysplasia. Dev Biol 321:64-76
Connerney, Jeannette; Andreeva, Viktoria; Leshem, Yael et al. (2008) Twist1 homodimers enhance FGF responsiveness of the cranial sutures and promote suture closure. Dev Biol 318:323-34