Glucocorticoid Regulation of Neurodevelopment.
Dr. DeFranco’s laboratory studies glucocorticoid receptor function focusing predominantly on the mechanisms of glucocorticoid receptor transactivation, interaction with coactivators, subcellular and subnuclear trafficking, interactions with molecular chaperones and processing. Over the years they have utilized various experimental model systems to provide novel mechanistic insights into receptor action. Some of their studies utilized neuronal cell systems and in particular, they were one of the first to provide direct demonstration of glucocorticoid receptor tethering to a DNA-bound transcription factor of the homeodomain family (i.e. Oct-1) utilizing a cell line of hypothalamic origin. Furthermore, using cells of hippocampal origin they provided one of the first demonstrations of developmentally regulated receptor degradation that is likely to be influenced by a receptor co-chaperone (e.g. CHIP). They have furthermore utilized state of the art molecular approaches (e.g. chromatin immunoprecipitation) to provide insights into receptor interactions with unique coregulator proteins (i.e. Hic-5) on chromatin. In recent years they have expanded their analysis of glucocorticoid receptor function to an area of clinical relevance. Clinical studies of postnatal and antenatal glucocorticoid administration and both in-vivo and in-vitro animal studies suggest that detrimental effects of these hormones on neural function in adults and juveniles may be caused by alterations in the proliferation and differentiation of embryonic neural stem cells. Specifically, the administration of glucocorticoids has been found to decrease the in-vitro and in vivo proliferative capacity of embryonic neural stem cells via cell cycle protein dependent processes and also alter the pattern and rate of neural stem cell differentiation. Various approaches (i.e. neural stem cell cultures, analysis and manipulation in mouse embryos, neuronal differentiation in vitro are being utilized to reveal molecular targets of genomic and nongenomic glucocorticoid receptor signaling and the mechanisms responsible for glucocorticoid regulation of embryonic neural stem cell function.
Ho, Y., Samarasinghe, R., Knoch, M., Lewis, M., Aizenman, E. and DeFranco, D.B. Selective inhibition of MAPK phosphatases by zinc accounts for ERK1/2-dependent oxidative neuronal cell death. Mol. Pharm. 74, 1141-1151, 2008.
Ho, Y., Logue, E.S., Callaway, C.W. and DeFranco, D.B. Different mechanisms regulating ERK activation in distinct brain regions following global ischemia and reperfusion. Neuroscience, 145, 248-255, 2007
Wang, X. and DeFranco, D.B. Alternative effects of the ubiquitin-proteasome pathway on glucocorticoid receptor downregulation and transactivation are mediated by the CHIP E3 ligase. Mol. Endocrinol. 19, 1474-1482, 2005.
Witchell, S. and DeFranco, D.B. (2006) Mechanisms of Disease: regulation of glucocorticoid hormone and receptor levels-impact on the metabolic syndrome. Nature Clin. Pract. Endocrinol. Metabol. 2, 621-631, 2006.
Cummings, C.J., Mancini, M.A., Antalffy, B., DeFranco, D.B., Orr, H.T. and Zoghbi, H.Y. Chaperone suppression of ataxin-1 aggregation and altered subcellular proteosome localization imply misfolding in SCA1. Nature Genet. 19, 148-154, 1998.