1. Transcriptional regulation of skeletal development.
My research involves the analysis of transcriptional regulatory networks that control cell differentiation events the control the formation of skeletal structures and how dysregulation of these networks cause developmental malformations. In particular, I am interested in the roles of forkhead box transcription factors FOXC1 and FOXC2 in chondrocyte and osteoblast differentiation. Development of the skeleton can proceed via two distinct mechanisms: endochondral and intramembranous ossification. Endochondral ossification involves the formation of a cartilaginous template (formed by chondrocytes) that is subsequently replaced by bone-forming osteoblasts. Intramembranous ossification involves the direct formation of bone-forming osteoblasts without a cartilage intermediate. Typically the long bones of the limbs and other components of the appendicular skeletal system arise through endochondral ossification, whereas craniofacial bones arise though intramembranous ossification.
FOXC1 and FOXC2 are critical regulators of both endochondral and intramembranous osteogenic development events. We utilize systems biology approaches to monitor differential gene expression in response to FOXC1 and FOXC2 loss of function, as well as using genome-wide analyses of transcription factor binding to identify key regulators of the chondrogenic and osteogenic differentiation programmes that are downstream of FOXC1 and FOXC2.
Once identified, the genes will be analyzed with respect to their effect on the differentiation of skeletal progenitor cells using molecular and cell biology approaches. Ultimately knowledge from these networks will be applied to the specific differentiation of stem cells into skeletal structures for regenerative medicine and tissue engineering purposes.
I am currently looking for students to study the roles of Forkhead transcription factor genes in skeletal development. We utilize a number of methodologies to study these processes including genetics, bioinformatics, molecular biology, and cell biology. If you are interested in research or in pursuing graduate studies in my lab, please feel free to contact me.
Berry, F.B., Lines, M.A., Oas, J.M., Footz, T., Underhill, D.A., Gage, P.J. and Walter, M.A. (2006) Functional interactions between FOXC1 and PITX2A underlie sensitivity to FOXC1 gene dosage effects in Axenfeld-Rieger Syndrome and anterior segment dysgenesis. Human Molecular Genetics 15: 905-19.
Berry, F.B., Mirzayans, F., and Walter, M.A. (2006) Regulation of FOXC1 stability and activity by an EGF activated MAP kinase signalling cascade. Journal of Biological Chemistry 281:10098-10104.
Tamimi, Y., Skarie J., Footz, T., Berry, F.B., Link, B.A., and Walter., M.A. (2006) FGF19 is a target for FOXC1 regulation in ciliary body derived cells. Human Molecular Genetics 15:3229-3240.
Berry, F.B., O’Neill, M.A, Coca-Prados, M. and Walter, M.A. (2005) FOXC1 transcriptional regulatory activity is impaired by PBX1 in a Filamin A mediated manner. Molecular and Cellular Biology 25:1415-24.
Berry, F.B., Tamimi, Y., Carle, M.V., Lehmann, O.J. and Walter, M.A. (2005). The establishment of a predictive mutational model of the Forkhead domain through the analyses of FOXC2 missense mutations identified in patients with hereditary lymphedema with distichiasis. Human Molecular Genetics 14: 2619-2627.
Saleem, R.A., Banerjee-Basu, S, Berry, F.B., Baxevanis, A.D. and Walter, M.A. (2003). Structural and functional analyses of disease-causing missense mutations in the forkhead domain of FOXC1. Hum. Mol. Genet. 12:2993-3005.
Berry, F.B., Saleem, R.A. and Walter, M.A. (2002) FOXC1 transcriptional regulation is mediated by N- and C-terminal activation domains and contains a phosphorylated transcriptional inhibitory domain. J. Biol. Chem. 277: 10292-97.