The primary objective of this proposal is to investigate the fundamental mechanisms that regulate mammalian craniofacial development. Craniofacial morphogenesis is regulated by complex interactions between the surface and neural ectoderms, endoderm, paraxial mesoderm and cranial neural crest. This process is highly dependent on the patterning information of emigrant cranial neural crest cells. The majority of craniofacial abnormalities are caused by defects in cranial neural crest cells that give rise to a variety of facial tissues and structures, including the cranial skull. Craniosynostosis affects 1 in ~2,500 infants and is 1 of the most common human congenital craniofacial deformities. Patients with craniosynostosis exhibit abnormal calvaria that are caused by defects in development of cranial suture and skull vault. Although genetic linkage analyses have provided some information on the molecular basis of craniosynostosis-related syndromes, very little is known about the biology of suture and skull development. In this proposal, we will study the genetic regulatory network that mediates calvarial morphogenesis and craniosynostosis in genetically modified mice. We have developed several mouse strains uniquely suited for these studies. Mutation of Axin2 severely affects formation of calvarial tissues and structures that are neural crest in origin. Phenotypic defects resembling craniosynostosis in humans developed in the mutants. Because of the abilities of Axin2 to negatively regulate the Wnt pathway by modulating the cellular levels of beta-catenin, we propose that the Wnt-Axin signaling network plays an important role in calvarial morphogenesis. We will elucidate the mechanism underlying suture development mediated by this signaling network. These studies promise new insights into the molecular mechanism of craniofacial development and human diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE015654-05
Application #
7835696
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Scholnick, Steven
Project Start
2006-07-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2012-05-31
Support Year
5
Fiscal Year
2010
Total Cost
$340,295
Indirect Cost
Name
University of Rochester
Department
Genetics
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Maruyama, Takamitsu; Jiang, Ming; Abbott, Alycia et al. (2017) Rap1b Is an Effector of Axin2 Regulating Crosstalk of Signaling Pathways During Skeletal Development. J Bone Miner Res 32:1816-1828
Maruyama, Takamitsu; Jeong, Jaeim; Sheu, Tzong-Jen et al. (2016) Stem cells of the suture mesenchyme in craniofacial bone development, repair and regeneration. Nat Commun 7:10526
Maruyama, Eri O; Lin, Heng; Chiu, Shang-Yi et al. (2016) Extraembryonic but not embryonic SUMO-specific protease 2 is required for heart development. Sci Rep 6:20999
Zhu, Xiao-Jing; Liu, Yudong; Yuan, Xueyan et al. (2016) Ectodermal Wnt controls nasal pit morphogenesis through modulation of the BMP/FGF/JNK signaling axis. Dev Dyn 245:414-26
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McGee-Lawrence, Meghan E; Carpio, Lomeli R; Bradley, Elizabeth W et al. (2014) Runx2 is required for early stages of endochondral bone formation but delays final stages of bone repair in Axin2-deficient mice. Bone 66:277-86
Li, T-F; Yukata, K; Yin, G et al. (2014) BMP-2 induces ATF4 phosphorylation in chondrocytes through a COX-2/PGE2 dependent signaling pathway. Osteoarthritis Cartilage 22:481-9
Sakamori, Ryotaro; Yu, Shiyan; Zhang, Xiao et al. (2014) CDC42 inhibition suppresses progression of incipient intestinal tumors. Cancer Res 74:5480-92
Zhu, Xiao-Jing; Liu, YuDong; Dai, Zhong-Min et al. (2014) BMP-FGF signaling axis mediates Wnt-induced epidermal stratification in developing mammalian skin. PLoS Genet 10:e1004687
McGee-Lawrence, Meghan E; Li, Xiaodong; Bledsoe, Krista L et al. (2013) Runx2 protein represses Axin2 expression in osteoblasts and is required for craniosynostosis in Axin2-deficient mice. J Biol Chem 288:5291-302

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