Transcriptional regulation of cardiac development and function using mouse models
Cardiac development, Neural crest, Transcription, Hypertrophy, Pax, Neurofibromatosis
The Epstein laboratory is interested in molecular mechanisms of cardiovascular development and stem cell biology, and the implications of these mechanisms for understanding human disease. Transgenic and knockout mouse models are used. One area of interest is the developmental biology of neural crest. Neural crest cells are multipotent progenitors that give rise to nerve, bone, muscle, melanocytes and other cell types. Hence, they are an attractive model for studying stem cell biology. Neural crest defects are associated with congenital heart disease. Using Cre-lox approaches, we have demonstrated that neural crest cells in mammals give rise to the smooth muscle of the great vessels and portions of the outflow tract of the heart. Semaphorins, molecules that mediate repulsive axon guidance in the central nervous system, also mediate proper neural crest patterning and we have identified novel semaphorin pathways functional in the vasculature. Neural crest patterning is affected in mouse models of DiGeorge syndrome, a common human congenital condition associated with congenital heart disease. We have studied mouse models of DiGeorge syndrome including those with deletions or mutations in the Tbx1 transcription factor gene. Another human disorder associated with neural crest defects is Type I Neurofibromatosis. We have demonstrated that heart defects in Nf1 mutant mice are related to a function for this gene in endothelial cells which is distinct from its role in neural crest. Our lab is also interested in transcriptional regulation of cardiac muscle development and function. We have discovered an unusual homeobox gene that affects heart growth and function. Knockouts in mice and zebrafish have poorly formed hearts, and over-expression in adults causes adult cardiac hypertrophy and heart failure. Chromatin remodeling of cardiac-specific genes is affected. More recent work focuses on the role of chromatin remodeling, histone deacetylation (HDACs) and a small homeodomain protein called Hopx that is expressed in adult stem cells. We have developed several outstanding core facilities for histology, transgenics and mouse physiology to aid students and postdocs in accomplishing research goals and in accelerating productivity.
Opportunities are available to analyze transgenic and knockout mice that serve as models of congenital and adult heart disease. Analysis is at the whole animal level and at the molecular level. Specific projects involve the investigation of Pax3, Hopx, Tbx1 and Nf1 function in cardiovascular and neural crest tissues. Assays involving protein-protein interactions, transcriptional regulation and chromatin modification are commonly used. Projects are tailored to students' experience and interests.
Kurt Allen Engleka
Degenhardt, K., Singh, M.K., Aghajanian, H., Massera, D., Wang, Q., Li, J., Li, L., Choi, C., Yzaguirre, A.D., Francey, L.J., Gallant, E., Krantz, I.D., Gruber, P.J., Epstein, J.A. : Semaphorin 3d signaling defects are associated with anomalous pulmonary venous connections. Nature Medicine 19(6): 760-5, Jun 2013.
Takeda, N., Jain, R., LeBoeuf, M.R., Padmanabhan, A., Wang, Q., Li, L, Lu, M.M., Millar, S., Epstein, J.A.: Hopx expression defines a subset of multipotent hair follicle stem cells and a progenitor population primed to give rise to K6+ niche cells. Development March 2013.
de la Pompa, J.L., Epstein, J.A. : Coordinating tissue interactions: notch signaling in cardiac development and disease Dev Cell 22(2): 244-54, Feb 2012.
de la Pompa, J., L., Epstein, J. A.: Coordinating tissue interactions: Notch signaling in cardiac development and disease. Developmental cell 22(2): 244-54, Feb 2012.
Engleka, K.A., Manderfield, L.J., Brust, R.D., Li, L., Cohen, A., Dymecki, S.M., Epstein, J.A.: Islet1 derivatives in the heart are of both neural crest and second heart field origin. Circulation research 110(7): 922-6, Mar 2012.
Manderfield, L.J., High, F.A., Engleka, K.A., Liu, F., Li, L., Rentschler, S., Epstein, J.A.: Notch activation of Jagged1 contributes to the assembly of the arterial wall. Circulation 125(2): 314-23, Jan 2012.
Shin, J., Padmanabhan, A., de Groh, E.D., Lee, J.S., Haidar, S., Dahlberg, S., Guo, F., He, S., Wolman, M.A., Granato, M., Lawson, N.D., Wolfe, S.A., Kim, S.H., Solnica-Krezel, L., Kanki, J.P., Ligon, K.L., Epstein, J.A., Look, A.T.: Zebrafish neurofibromatosis type 1 genes have redundant functions in tumorigenesis and embryonic development. Dis Model Mech Nov 2012.
Loscalzo, J., Libby, P., Epstein, J.: Basic Biology of the Cardiovascular System. Harrison’s Texbook of Medicine. D.L. Longo, H.T. Randolf, (eds.). The McGraw Hill Companies, Inc. 18th ed.,: 1798-1811, 2011.
Rentschler, S., Harris, B.S., Kuznekoff, L., Jain, R., Manderfield, L., Lu, M.M., Morley, G.E., Patel, V.V., Epstein, J.A.: Notch signaling regulates murine atrioventricular conduction and the formation of accessory pathways. J Clin Invest 121(2): 525-33, Feb 2011.
Takeda, N.i, Jain, R., LeBoeuf, M.R., Wang, Q., Lu,,M.M., Epstein, J.A.: Interconversion between intestinal stem cell populations in distinct niches. Science 334(6061): 1420-4, Dec 2011.
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Last updated: 01/18/2017
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