Craniofacial skeletal development is specified by a coordinated temporal and spatial pattern of gene expression. It involves both intramembranous and endochondral ossification. Ultimately, secreted morphogens such as transforming growth factor beta, bone morphogenetic proteins, hedgehog proteins and wingless proteins signal to key transcription factors to specify gene expression. The comparative phenotypic study of human and mouse genetic craniofacial skeletal malformation syndromes is a powerful approach for dissecting these signaling pathways. Two such syndromes, cleidocranial dysplasias (CCD) and trichorhinophalangeal syndrome (TRPS) are caused by mutations in transcription factors RUNX2 and TRPS1 that are important in craniofacial skeletogenesis. The two phenotypes exhibit distinct as well as common clinical features that point to potential biochemical and genetic interaction. Based on our preliminary studies, we hypothesize that TRPS1 serves a critical function in specifying chondrogenic mesenchymal condensations and chondrocyte differentiation including during chrondrocyte hypertrophy, though additional functions in proliferating chondrocytes and/or bone cannot yet be excluded. Furthermore, we hypothesize that Trpsl may accomplish this by modifying RUNX2 function in an antagonistic fashion.
Our Specific Aims are to 1) characterize the craniofacial skeletal and dental phenotype of already generation Trpsl mutant mice on a histological and molecular level, 2) evaluate the consequence of overexpression of Trps1 in proliferating and hypertropic chondrocytes in vivo, 3) determine the context dependence of TRPS1 repression of RUNX2 both in vivo with transgenic mice and in vitro with cell models of osteoblast differentiation, and 4) determine whether TRPS1 and RUNX2 interact genetically by generating double mutant animals and biochemically by immunoprecipitation and protein binding studies. These studies will answer two important questions: What is the function of TRPS1 during craniofacial skeletal development? How does TRPS1 regulate RUNX2 activity? By combining human clinical genetics with mouse genetic and cellular approaches, these studies will provide new perspectives into the transcriptional mechanisms that govern craniofacial skeletal development including mesenchymal cell fate commitment and regulation of chrondrocyte hypertrophy.
| Chen, Shan; Grover, Monica; Sibai, Tarek et al. (2015) Losartan increases bone mass and accelerates chondrocyte hypertrophy in developing skeleton. Mol Genet Metab 115:53-60 |
| Tao, Jianning; Jiang, Ming-Ming; Jiang, Lichun et al. (2014) Notch activation as a driver of osteogenic sarcoma. Cancer Cell 26:390-401 |
| Chen, Shan; Lee, Brendan H; Bae, Yangjin (2014) Notch signaling in skeletal stem cells. Calcif Tissue Int 94:68-77 |
| Yang, Tao; Grafe, Ingo; Bae, Yangjin et al. (2013) E-selectin ligand 1 regulates bone remodeling by limiting bioactive TGF-? in the bone microenvironment. Proc Natl Acad Sci U S A 110:7336-41 |
| Chen, Shan; Tao, Jianning; Bae, Yangjin et al. (2013) Notch gain of function inhibits chondrocyte differentiation via Rbpj-dependent suppression of Sox9. J Bone Miner Res 28:649-59 |
| Ruan, Merry Z C; Dawson, Brian; Jiang, Ming-Ming et al. (2013) Quantitative imaging of murine osteoarthritic cartilage by phase-contrast micro-computed tomography. Arthritis Rheum 65:388-96 |
| Napierala, Dobrawa; Sun, Yao; Maciejewska, Izabela et al. (2012) Transcriptional repression of the Dspp gene leads to dentinogenesis imperfecta phenotype in Col1a1-Trps1 transgenic mice. J Bone Miner Res 27:1735-45 |
| Bae, Yangjin; Yang, Tao; Zeng, Huan-Chang et al. (2012) miRNA-34c regulates Notch signaling during bone development. Hum Mol Genet 21:2991-3000 |
| Li, Feifei; Lu, Yaojuan; Ding, Ming et al. (2011) Runx2 contributes to murine Col10a1 gene regulation through direct interaction with its cis-enhancer. J Bone Miner Res 26:2899-910 |
| Homan, Erica P; Rauch, Frank; Grafe, Ingo et al. (2011) Mutations in SERPINF1 cause osteogenesis imperfecta type VI. J Bone Miner Res 26:2798-803 |
Showing the most recent 10 out of 21 publications
