Roland Baron, D.D.S, Ph.D.

Professor of Orthopaedics and Cell Biology
Baron lab website Phone: (203) 785-5986 Assistant: (203) 785-5986 Lab: (203) 785-5026 Fax: (203) 785-2744 e-mail: roland.baron@yale.edu		Department of Orthopaedics and Rehabilitation Yale University School of Medicine 800 Howard Avenue New Haven, CT 06519-1369 USA <Courier Address> 333 Cedar Street, SHM IE-55 New Haven, CT 06510-3206

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Our laboratory is entirely focused on signal transduction and the ways in which it controls cell differentiation and function. For this purpose, we mostly study skeletal development and remodeling as a model system. In this context, the program of the laboratory is divided in three well-defined but highly interactive main research goals:

• Understanding the role of the AP1 family of transcription factors, specifically Delta FosB, in skeletal development and in particular in the determination of mesenchymal cell lineages between the osteoblast and adipocyte cell types.
• Characterizing the role of Src tyrosine kinase and its substrate Cbl in the signaling from integrins and other receptors involved in cell adhesion and migration, the role of ubiquitination in these processes and the role of these processes in cell migration, using as a model system the migration and function of the bone resorbing cell, the osteoclast.
• Characterizing the molecular mechanisms by which the G Protein-coupled calcitonin receptor regulates the cytoskeleton, adhesion and migration in osteoclasts, and its cross-talk with integrin signaling, Src, Cbl and the focal adhesion kinase Pyk2.

Our approaches combine extensively in vitro and in vivo experiments, often involving genetically modified transgenic or knockout mice and their isolated cells, that integrate molecular, cellular and in vivo studies to determine both the molecular mechanisms of cell biology and pathology and the impact of these mechanisms and their alteration at the organ level in normal and disease conditions. Our work is directly relevant to several medical issues such as osteoporosis, bone metastasis in cancer, cancer itself through our focus on several proto-oncogenes, and endocrine disorders.

Selected Publications

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Marzia M., Chiusaroli R., Neff L., Kim N.Y., Chishti A.H. , Baron R., and Horne W.C. Calpain is required for normal osteoclast function and is downregulated by calcitonin. J. Biol. Chem. 281:9745-54, 2006.

Morvan F., Clement-Lacroix P., Roman Roman S., Boulukos K., Suc-Royer I., Vayssiere B., Ammann P., Martin P., Pinho S., Pgnonec P., Mollat P., Niehrs C., Baron R. and Rawadi G. Deletion of a single allele of the Dkk1 gene  leads to an increase  in bone formation and bone mass. J. Bone  Miner. Res.  21:934-45, 2006.

Aoki K., Saito H., C. Itzstein,  M.Ishiguro, T. Shibata, R. Blanque , P. Mollat,  A. H. Mian, M. Takahashi, Y. Suzuki, M. Yoshimatsu , A. Yamaguchi, P. Deprez, P. Mollat, R. Murali, K. Ohya, W. C. Horne , and R. Baron : A TNF Receptor Loop Peptide Mimic Blocks RANK Ligand-induced Signaling, Bone Resorption and Bone Loss . J. Clin. Invest. 116:1525-34, 2006.

Baron R. FSH versus Estrogen: Who’s guilty of breaking bones? Cell Metabolism , 3:302-305, 2006.

Baron R., Rawadi G. and Roman-Roman S. Wnt signaling: A key regulator of bone formation. Curr. Top. Dev.  Biol. 76:103-127, 2006.

Miyazaki T., Tanaka S., Sanjay A. and Baron R. The role of Src kinase in osteoclast function. Mod. Rheumatol., 16:68-74, 2006.

Windahl S., Galien R., Chiusaroli R., Clément-Lacroix P.,  Morvan F., Lepescheux L., Nique F., Horne W.C., Resche-Rigon M. and Baron R. Bone protection by estrens occurs through non-tissue selective activation of the androgen receptor. J. Clin. Invest. 116:2500-9, 2006.

Sanjay A., Miyazaki T., Itzstein C., Purev E., Horne W.C. and Baron R. Identification and functional characterization of a Src SH3 domain-binding site on Cbl. FEBS Journal , 273: 5442-5456, 2006.
229. Hay E., Faucheu C., Suc-Royer I., Touitou R., Stiot V., Vayssiere B., Baron R., Roman-Roman S. and Rawadi G. Interaction  between  LRP5 and Frat1 mediates the activation of the Wnt canonical pathway. J. Biol. Chem. 280:13616-13623,  2005.

Baron R. and Horne W.C. Regulation of osteoclast activity. In Bone Resorption, F.Bronner, M.C. Farach-Carson and J. Rubin Editors, Springer Verlag London Limited publisher, pp 34-57, 2005

Seck T., Pellegrini M., Florea A.M., Grignoux V., Baron R., Mierke D.F. and Horne W.C. The Delta e13 isoform of the calcitonin receptor forms a six transmembrane domain receptor with dominant negative effects on receptor surface expression and signaling. Mol. Endocrinol. 19:2132-2144, 2005

Bruzzaniti A., Neff L., Sanjay A., Horne W.C., De Camilli P. and Baron R. Dynamin forms a Src-kinase-sensitive complex with Cbl and regulates podosomes and osteoclast activity. Mol. Biol. of the Cell 16:3301-3313, 2005

Horne W.C., Sanjay. A, Bruzzaniti A. and Baron R. The role of Src and Cbl in osteoclast biology. Immunological Reviews  208:106-125, 2005.

Clement-Lacroix P., Ai M., Morvan F., Roman-Roman S., Vayssiere B., Belleville C., Estrera K., Warman M., Baron R . and Rawadi G. LRP5-independent activation of Wnt signaling by Lithium chloride increases bone formation and bone mass in mice. Proc. Nat. Acad. Sci USA 102:17406-17411, 2005

Baron R. (2004)  Arming the osteoclast.Nat Med. 10(5):458-60.

Miyazaki T, Sanjay A, Neff L, Tanaka S, Horne WC, Baron R. (2004)Src kinase activity is essential for osteoclast function. J Biol Chem. 279(17): 17660-6.

Kveiborg M, Sabatakos G, Chiusaroli R, Wu M, Philbrick WM, Horne WC,Baron R. (2004) Delta FosB induces osteosclerosis and decreases adipogenesis by two independent cell autonomous mechanisms. Mol Cell Biol. 24:2820-30.

Chiusaroli R, Knobler H, Luxenburg C, Sanjay A, Granot-Attas S. Tiran Z, Miyazaki T, Harmelin A, Baron R* and Elson A* (2004)Tyrosine phosphatase epsilon is a positive regulator of osteoclast function in vitro and in vivo. Mol Biol Cell. 15:234-244.  

Akiyama T, Bouillet P, Miyazaki T, Kadono Y, Chikuda H, Chung UI, Fukuda A, Hikita A, Seto H, Okada T, Inaba T, Sanjay A, Baron R, Kawaguchi H, Oda H, Nakamura K, Strasser A, Tanaka S. (2003) Regulation of osteoclast apoptosis by ubiquitination of proapoptotic BH3-only Bcl2 family member Bim. EMBO J. 22(24):6653-64.

Chiusaroli R, Sanjay A, Henriksen K, Engsig MT, Horne WC, Gu H, Baron R. (2003)Deletion of the gene encoding c-Cbl alters the ability of osteoclasts to migrate, delaying resorption and ossification of cartilage during the development of long bones. Dev Biol. 261(2): 537-47.

Roman-Roman S, Garcia T, Jackson A, Theilhaber J, Rawadi G, Connolly T, Spinella-Jaegle S, Kawai S, Courtois B, Bushnell S, Auberval M, Call K, Baron R. (2003)Identification of genes regulated during osteoblastic differentiation by genome-wide expression analysis of mouse calvaria primary osteoblasts in vitro. Bone. 32(5): 474-82.

Miyazaki T, Neff L, Tanaka S, Horne WC, Baron R. (2003)Regulation of cytochrome c oxidase activity by c-Src in osteoclasts. J Cell Biol. 160(5): 709-18.

Bard F, Patel U, Levy JB, Jurdic P, Horne WC, Baron R. (2002)Molecular complexes that contain both c-Cbl and c-Src associate with Golgi membranes. Eur J Cell Biol. 81(1): 26-35.

Sanjay A, Horne WC, Baron R. (2001) The Cbl family: ubiquitin ligases regulating signaling by tyrosine kinases. Science (STKE). 2001(110): PE40. Review.

Yokouchi M, Kondo T, Sanjay A, Houghton A, Yoshimura A, Komiya S, Zhang H, Baron R. (2001)Src-catalyzed phosphorylation of c-Cbl leads to the interdependent ubiquitination of both proteins. J Biol Chem. 276(37): 35185-93.

Sanjay A, Houghton A, Neff L, DiDomenico E, Bardelay C, Antoine E, Levy J, Gailit J, Bowtell D, Horne WC, Baron R. (2001)Cbl associates with Pyk2 and Src to regulate Src kinase activity, alphavß3 integrin-mediated signaling, cell adhesion, and osteoclast motility. J Cell Biol. 2001 152(1): 181-95.

Sabatakos G, Sims NA, Chen J, Aoki K, Kelz MB, Amling M, Bouali Y, Mukhopadhyay K, Ford K, Nestler EJ, Baron R. (2000)Overexpression of DeltaFosB transcription factor(s) increases bone formation and inhibits adipogenesis. Nat Med. 6(9): 985-90.