Executive Vice Dean and Chief Scientific Officer
Transcriptional regulation of cardiac development and function using mouse models
Cardiac development, Neural crest, Transcription, Hypertrophy, Pax, Neurofibromatosis.
The Epstein Lab
studies molecular mechanisms of neural crest and cardiac development, with a particular interest in applying lessons learned from developmental models to the understanding and therapy of adult diseases. One area of interest relates to the role of the Pax3 transcription factor in neural crest cells. Neural crest can differentiate into a multitude of cell types including nerve, bone, vascular smooth muscle and melanocytes. Defects in neural crest, and mutations in Pax3, can lead to common forms of congenital heart disease. We have used mouse models to elucidate a molecular cascade involved in cardiac neural crest migration and differentiation, implicating members of the BMP, Notch, Semaphorin, myocardin and T-box families in this process. This work has direct relevance to the understanding of the genetic basis of congenital heart disease.
We have also used neural crest as a model of stem cell biology, and we have identified adult neural crest stem cells that reside in the hair follicle and give rise to regenerating melanocytes. Here, Pax3 plays a critical role both in determining cell-fate specification, and also in maintaining the undifferentiated stem cell phenotype until external signals, including induced by Wnt signals, trigger changes in transcriptional complexes and melanocyte differentiation.
Our studies have implicated important interactions between neural crest and other cell types, including vascular endothelium. We have discovered a novel member of the Plexin/Semaphorin family, PlexinD1, expressed by endothelial cells that is required for normal cardiovascular patterning. We have also demonstrated a critical endothelial function for the product of the type 1 Neurofibromatosis gene (NF1), which is a tumor suppressor gene mutated in von Recklinghausen Neurofibromatosis, a disease characterized by neural crest tumors and cardiovascular defects. This work has led to the appreciation for Ras signaling in epithelial-mesenchymal transformation in the heart and suggests that a common mechanism of cardiovascular defects in a series of childhood disorders, including Noonan’s syndrome and NF1. We are also using zebrafish models to exploit the ease of evaluation of the developing vasculature in our NF1 and Plexin studies.
Application of the elucidation of embryonic programs to adult disease is best exemplified by our work with a novel homeodomain factor called HOP. HOP is expressed early in cardiac development, but also functions in adult cardiac hypertrophy, and it is significantly down-regulated in human heart failure. HOP functions in association with HDAC2, a member of the histone deacetylase chromatin remodeling family. We have shown that HDAC inhibitors are potent anti-hypertensive agents, and our ongoing work suggests that HDAC2 is a critical molecular target of HDAC inhibitors in the heart. Our work suggests that HOP and HDAC2 regulate the fetal gene program during development, and again in the setting of adult disease when the fetal program is reactivated. Evaluation of these adult mouse models of heart disease is facilitated by imaging, microsurgery and invasive hemodynamic and electrophysiologic techniques that we have developed or refined to mimic all of the diagnostic tools available to the human adult cardiologist allowing us to develop new therapeutic targets for congestive heart failure.
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: 06/10/2016
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