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Clemencia Colmenares, Ph.D.
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Area of general research interest:
Role of c-ski proto-oncogene in growth and development.
Current program:
- Disruption of c-ski Functions in Cells and Mice.
- Differentiation of Embryonic Stem Cells in Vitro.
Investigators:
- Huayun Deng, Ph.D., Research Fellow
- Lisa Ruple, Research Technician
Collaborators:
- Edward Stavnezer, Ph.D., Department of Biochemistry, Case Western Reserve University
Brief Description:
My laboratory studies the transcriptional control of gene expression during development. We focus on mouse craniofacial and musculoskeletal development. We use knockout mice lacking the Ski oncoprotein as a model for a human microdeletion syndrome because the mutant mouse mimics many of the abnormalities reported in patients with 1p36 monosomy.
The Ski proto-oncogene encodes a transcriptional cofactor shown to co-repress multiple networks, including the transforming growth factor-β/bone morphogenic protein (TGF-β/BMP), Wnt, and retinoic acid (RA) signaling pathways. Our work uses both genetic approaches and developmental analyses of gene expression. Ski-/- mice exhibit very different craniofacial defects depending on the genetic background: C57BL/6J congenics show highly penetrant midline facial clefting and delayed fontanel closure, whereas with a 129 background, Ski-/- mice show exencephaly instead. A genome scan of F2 Ski-/- offspring has identified highly significant candidate modifier loci.
We are now working to identify the specific genes in these regions with modifier activity and are examining loci associated with facial clefting in humans. This work is complemented by developmental studies of gene expression to test the hypothesis that in the absence of Ski, aberrant regulation of the TGF-β/BMP and RA pathways causes defects in neural crest migration, leading to abnormal development of the face, skull, and/or neural tube.
We are also studying the mechanisms underlying other phenotypes relevant to human abnormalities, such as ocular defects and cardiac outflow tract malformations.
Key References:
Namciu, S., Lyons, G.E., Micales, B.K., Heyman, H.C., Colmenares, C., and Stavnezer, E. (1995). Enhanced expression of mouse c-ski accompanies terminal skeletal muscle differentiation in vivo and in vitro. Dev. Dyn. 204, 291-300.
Tarapore, P., Richmond, C., Zheng, G., Cohen, S.B., Kelder, B., Kopchick, J., Kruse, U., Sippel, A.E., Colmenares, C., and Stavnezer, E. (1997). DNA binding and transcriptional activation by the Ski oncoprotein mediated by interaction with NFI. Nucleic Acids Res. 25, 3895-3903.
Zheng, G., Teumer, J., Colmenares, C., Richmond, C., and Stavnezer, E. (1997). Identification of a core functional and structural domain of the v-Ski oncoprotein responsible for both transformation and myogenesis. Oncogene 15, 459-471.
Berk, M., Desai, S.Y., Heyman, H.C., and Colmenares, C. (1997). Mice lacking the ski proto-oncogene have defects in neurulation, craniofacial patterning, and skeletal muscle development. Genes Dev. 11, 2029-2039.
Nomura, T., Khan, M.M., Kaul, S.C., Dong, H.D., Wadhwa, R., Colmenares, C., Kohno, I., and Ishii, S. (1999). Ski is a component of the histone deacetylase complex required for transcriptional repression by Mad and thyroid hormone receptor. Genes Dev. 13, 412-423.
Shinagawa, T., Nomura, T., Colmenares, C., Ohira, M., Nakagawara, A., and Ishii, S. (2001). Increased susceptibility to tumorigenesis of ski-deficient heterozygous mice. Oncogene 20, 8100-8108.
Kokura, K., Kaul, S.C., Wadhwa, R., Nomura, T., Khan, M.M., Shinagawa, T., Yasukawa, T., Colmenares, C., and Ishii, S. (2001). The Ski protein family is required for MeCP2-mediated transcriptional repression. J. Biol. Chem. 276, 34115-34121.
Colmenares, C., Heilstedt, H.A., Shaffer, L.G., Schwartz, S., Berk, M., Murray, J.C., and Stavnezer, E. (2002). Loss of the SKI proto-oncogene in individuals affected with 1p36 deletion syndrome is predicted by strain-dependent defects in Ski(-/-) mice. Nat. Genet. 30, 106-109.
Dai, P., Shinagawa, T., Nomura, T., Harada, J., Kaul, S.C., Wadhwa, R., Khan, M.M., Akimaru, H., Sasaki, H., Colmenares, C., and Ishii, S. (2002). Ski is involved in transcriptional regulation by the repressor and full-length forms of Gli3. Genes Dev. 16, 2843-2848.
Chen, D., Xu, W., Bales, E., Colmenares, C., Conacci-Sorrell, M., Ishii, S., Stavnezer, E., Campisi, J., Fisher, D.E., Ben Ze'ev, A., and Medrano, E.E. (2003). SKI activates Wnt/beta-catenin signaling in human melanoma. Cancer Res. 63, 6626-6634.
Atanasoski, S., Notterpek, L., Lee, H.Y., Castagner, F., Young, P., Ehrengruber, M.U., Meijer, D., Sommer, L., Stavnezer, E., Colmenares, C., and Suter, U. (2004). The protooncogene ski controls Schwann cell proliferation and myelination. Neuron 43, 499-511.
McGannon, et al. Ocular abnormalities in mice lacking the Ski proto-oncogene. Invest Ophthalmol Vis Sci 2006;47:4231-7.