Donald B. DeFranco, PhD

  • Professor and Vice Chair, Pharmacology & Chemical Biology, Neuroscience

Phone

412-624-4259

E-mail

dod1@pitt.edu

Personal Website

website link

Education & Training

PhD, Yale University (1981)

Campus Address

7041 Biomedical Science Tower 3

One-Line Research Description

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.

Representative Publications

Carson RA, Rudine AC, Tally SJ, Franks AL, Frahm KA, Waldman JK, Silswal N, Burale S, Phan JV, Chandran UR, Monaghan AP & DeFranco DB (2018). Statins impact primary embryonic mouse neural stem cell survival, cell death and fate through distinct mechanisms. PLoSONE, 13(5):e0196387.

Carson R, Monaghan-Nichols P, DeFranco DB & Rudine AC (2016) Effects of antenatal steroids on the developing brain. Steroids114, 25-32.

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.

Frahm KA, Peffer ME, Zhang JY, Luthra S, Chakka AB, Couger MB, Chandran UR, Monaghan AP & DeFranco DB (2016). The dexamethasone transcriptome in hypothalamic embryonic neural stem cells. Molecular Endocrin. 30, 144-154. PMCID:  PMC4695633

Frahm KA, Waldman JK, Luthra S, Rudine AC, Monaghan-Nichols AP, Chandran UR & DeFranco DB (2018). A comparison of sexually dimorphic dexamethasone transcriptome in mouse cerebral cortical and hypothalamic embryonic neural stem cells. Mol. Cell. Endocrinol. S0303-7207, 30295.
 
Solomon JD, Heitzer MD, Liu TT, Beumer JH, Parise RA, Normolle DP, Leach DA, Buchanan G and DeFranco DB.  VDR activity is differentially affected by Hic-5 in prostate cancer and stromal cells. Mol Cancer Res 12:1166-1180, 2014.

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

Liu TT, Grubisha MJ, Frahm KA, Wendell SG, Liu J, Ricke WA, Auchus RJ & DeFranco DB (2016). Opposing effects of cyclooxygenase-2 on estrogen receptor-ß response to 5a-reductase inhibition in prostate epithelial cells. J. Biol. Chem, in press.

Leach DA, Need EF, Toivanen R, Trotta AP, Palenthorpe HM, Tamblyn DJ, Kopsaftis T, England GM, Smith E, Drew PA, Pinnock CB, Lee P, Holst J, Risbridger GP, Chopra S, DeFranco DB, Taylor RA and Buchanan G.  Stromal androgen receptor regulates the composition of the microenvironment to influence prostate cancer outcome.  Oncotarget 6:16135-16150, 2015.

Peffer ME, Zhang JY, Umfrey L, Rudine AC, Monaghan AP, DeFranco DB (2015). The impact of antenatal therapeutic synthetic glucocorticoids on the developing fetal brain. Mol. Endocrinol. 29, 658-666.

Peffer ME, Chandran UR, Luthra S, Volonte D, Galbiati F, Garabedian MJ, Monaghan AP and DeFranco DB.  Caveolin-1 regulates genomic action of the glucocorticoid receptor in neural stem cells.  Mol Cell Biol 34:2611-2623, 2014.

Samarasinghe RA, Di Maio R, Volonte D, Galbiati, F, Lewis M, Romero G, DeFranco DB (2011). Non-genomic glucocorticoid receptor action regulates gap junction intercellular communication and neural progenitor cell proliferation. Proc. Natl. Acad. Sci. USA 108, 16657-16662.

Samarasinghe RA, Kanuparthi PS, Greenamyre JT, DeFranco DB & Di Maio R (2014). Transient muscarinic and glutamatergic stimulation of neural stem cells trigger acute and persistent changes in differentiation. Neurobiol. Disease70, 252-261.

Tsiarli MA, Monaghan-Nichols AP, DeFranco DB (2014). Differential subcellular localization of the glucocorticoid receptor in distinct neural stem and progenitor populations of the mouse telencephalon in vivo. Brain Research 1523, 10-27.

Tsiarli MA, Rudine A, Kendal N, Pratt MO, Krall R, Thiels E, DeFranco DB & Monaghan AP (2017). Antenatal dexamethasone exposure differentially affects distinct cortical neural progenitor cells and triggers long-term changes in cerebral architecture and behavior. Transl. Psychiatry 7, e1153.

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.