During the last few years, much has been learned about the mechanisms that regulate the formation of the skeletal tissues. Several transcription factors critical to the chondrogenic and osteogenic program have been identified, and the importance of various growth factors and cytokines in these processes is also being established. My laboratory has recently established an important role for the retinoid signaling pathway in chondrogenesis (Weston et al, 2000, J. Cell Biol.; Weston et al. 2002, J. Cell Biol.) and recent evidence from our laboratory also demonstrates an important function for this pathway in osteogenesis (Sampaio and Underhill, in preparation). To better understand the mechanisms underlying the commitment and differentiation of skeletal progenitors, my lab has employed a functional genomics approach. Traditionally, the major limitation of this approach involves efficiently defining the function of potentially hundreds of differentially-expressed candidate genes. To circumvent this problem, the Underhill lab has developed various high-content screens to facilitate the analysis of gene function in chondrogenesis and osteogenesis. In this manner, hundreds-thousands of genes can be screened for their ability to promote or inhibit these programs. This approach together with complementary strategies (ie. transcriptional profiling with arrays, automation with robotics, etc.), are currently being used to delineate the molecular regulatory networks that underlie the formation of chondrocytes and osteoblasts. Such information is expected to contribute substantially to our basic understanding of skeletal development and remodeling, but will also lead to the identification of novel targets which will serve as new therapeutic avenues for the manipulation of the skeletal cell phenotype.

Nohe A, Keating E, Underhill TM, Knaus P & Petersen NO. (2005) Dynamics and interaction of caveolin-1 isoforms with BMP-receptors. J. Cell Science 118(3):643-50.

Stanton LA, Sabari S, Sampaio AV, Underhill TM & Beier F. (2004) p38 MAP kinase signaling is required for hypertrophic condrocyte differentiation. Biochemical Journal 378(1):53-62.

Jay KE, Rouleau A, Underhill TM & Bhatia M. (2004) Identification of a novel population of primitive human cord blood cells with hematopoieticytic and chondrocytic potential. Cell Research 14:268-82.

Woods A, James C, Underhill TM & Beier F. (2004) Identification of the putative collagen X gene from the pufferfish Fugu rubripes. Gene 342:77-83.

Nohe, A., Keating, E., Loh, C., Underhill, T.M., Knaus, P. and Petersen, N.O. (2004) Caveolin-1 reorganization studied by image correlation spectroscopy. Faraday Discussions126:185-95.

Weston, A.D., Sampaio, A.V., Ridgeway, A.G., and Underhill, T.M. (2003) Inhibition of p38 MAPK signaling promotes muscle formation. Journal of Cell Science, 166:2885-93.

Weston, A.D., Blumberg, B., and Underhill, T.M. (2003) Active repression by unliganded retinoid receptors in development: less is sometimes more. Journal of Cell Biology, 161:233-8.

Nohe, A., Keating, E., Underhill, T.M., Knaus, P. and Petersen, N.O. (2003) Effect of the distribution and clustering of BMP receptors on the activation of signaling pathways. Journal of Cell Science, 166:3277-84.

Weston, A.D., Hoffman, L.M. and Underhill, T.M. (2003) Revisiting the role of the retinoid signaling pathway in skeletal development. Birth Defects Research, Part C: Embryo Today: Reviews, 69: 156-173.

Hoffman, L.M., Weston, A.D. and Underhill, T.M. (2003) Molecular mechanisms regulating chondroblast differentiation. Journal of Bone & Joint Surgery 85-A (Supp. 2): 124-132.

Brown, K., Chen, Y., Underhill, T.M., Mymyrk, J.S., Torchia, J. (2003) The coactivator p/CIP/SRC-3 facilitates retinoic acid receptor signalling via recruitment of GCN5. Journal of Biological Chemistry, 278(41):39402-12. 

Wongtrakool, C., Malpel, S., Gorenstein, J., Sedita, J., Ramirez, M.I., Underhill, T.M., Cardoso, W.V. (2003) Downregulation of RARalpha is required for sacculation and type I cell formation in the developing lung. Journal of Biological Chemistry, 278(47):46911-8.

Weston, A.D., Chandraratna, R.A.S., Torchia, J. and Underhill, T.M. (2002) Requirement for RAR-mediated gene repression in skeletal progenitor differentiation. Journal of Cell Biology 158(1): 39-51.

Weston, A.D., Rosen, V., Chandraratnas, R.A.S. and Underhill, T.M. (2000) Regulation of skeletal progenitor differentiation by the BMP and retinoid signaling pathways. Journal of Cell Biology, 148:601-612.