This proposal continues our efforts to elucidate the genetic regulatory network underlying craniofacial development. The craniofacial skeleton consists of viscerocranium and neurocranium, which is subdivided into the calvarium/skull vault and chondrocranium/skull base. During development of the calvarium, cranial sutures serve as growth centers for skeletogenesis. Defects in suture morphogenesis resulting in premature closure are causally linked to congenital craniofacial deformities in humans. Although human genetic analyses have identified genes involved in pathogenesis of these diseases, little is known about the regulation of suture closure which is essential for development of a healthy skull. In the previously proposed investigation, we have linked the canonical Wnt pathway to calvarial development by showing that Axin2-deficient mice exhibit suture defects resembling craniosynostosis in humans. Axin2/?-catenin signaling regulates the expansion of suture stem cells and their subsequent developmental processes. Knockout of Axin2 also results in induction of the synostosis-related genes, including those encoding members of the FGF receptor family. Mutations in these genes have been linked to synostosis-related syndromes in humans and mice. We have further shown that the balance of Wnt and FGF is essential for determining the lineage commitment of suture stem cells during calvarial development. The results identify endochondral ossification caused by switching the stem cell fate as a mechanism of suture closure during development and implicate this process in craniosynostosis. Our findings have led us to propose a model in which the interplay of Wnt, FGF and BMP signaling is essential for orchestrating the calvarial morphogenetic regulatory network. In this proposal, we will continue to elucidate the mechanism underlying calvarial morphogenesis coordinately mediated by these pathways in health and disease.
Three specific aims are designed to: 1) define the role of BMP signaling as a key determinant in development of suture mesenchyme;2) elucidate the mechanism underlying the crosstalk of BMP and FGF signaling in calvarial morphogenesis;3) determine the role of Gpr177 in Wnt-mediated development of craniofacial skeleton.
This proposal investigates the basic genetic elements controlling the formation of a healthy skull during craniofacial skeletogenesis. Using genetically modified mouse strains, we elucidate the mechanism underlying the interplay of three evolutionary conserved signal transduction pathways in normal development and pathogenesis of the skull vault. The results obtained in our study are highly relevant to the health of human development in craniofacial deformities, such as craniosynostosis and cleiocranial dysplasia, and has potentials to gain insights into therapeutic strategies for human diseases.
|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|
|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|
|Sakamori, Ryotaro; Yu, Shiyan; Zhang, Xiao et al. (2014) CDC42 inhibition suppresses progression of incipient intestinal tumors. Cancer Res 74:5480-92|
|Jiang, Ming; Ku, Wei-yao; Fu, Jiang et al. (2013) Gpr177 regulates pulmonary vasculature development. Development 140:3589-94|
|Zhu, XiaoJing; Zhao, Pan; Liu, YuDong et al. (2013) Intra-epithelial requirement of canonical Wnt signaling for tooth morphogenesis. J Biol Chem 288:12080-9|
|Maruyama, Takamitsu; Jiang, Ming; Hsu, Wei (2013) Gpr177, a novel locus for bone mineral density and osteoporosis, regulates osteogenesis and chondrogenesis in skeletal development. J Bone Miner Res 28:1150-9|
|Fu, Jiang; Hsu, Wei (2013) Epidermal Wnt controls hair follicle induction by orchestrating dynamic signaling crosstalk between the epidermis and dermis. J Invest Dermatol 133:890-8|
|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|
|Zhang, Yong-guo; Wu, Shaoping; Xia, Yinglin et al. (2012) Axin1 prevents Salmonella invasiveness and inflammatory response in intestinal epithelial cells. PLoS One 7:e34942|
|Fu, Jiang; Ivy Yu, Hsiao-Man; Maruyama, Takamitsu et al. (2011) Gpr177/mouse Wntless is essential for Wnt-mediated craniofacial and brain development. Dev Dyn 240:365-71|
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