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Research

P3CreKI Our laboratory 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.

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Publications

For all publications, click on PubMed

Latest Publications:

Kook, H., Yung, W.W., Simpson, R.J., Kee, H.J., Shin, S., Lowry, J., Loughlin, F.E., Epstein, J.A., Mackay, J.P. Analysis of the structure and function of the transcriptional co-regulator HOP.  Biochemistry. 2006 Sep 5;45(35):10584-90.

Yin Z., Gonzales L., Kolla V., Rath N., Zhang Y., Lu M.M., Kimura S., Ballard P.L., Beers M.F., Epstein J.A., Morrisey E.E. Hop functions downstream of Nkx2.1 and GATA6 to mediate HDAC-dependent negative regulation of pulmonary gene expression. Am J Physiol Lung Cell Mol Physiol. 2006 Aug;291(2):L191-9.

Ismat F.A., Xu J., Lu M.M., Epstein J.A. The neurofibromin GAP-related domain rescues endothelial but not neural crest development in Nf1 mice.  J Clin Invest. 2006 Sep;116(9):2378-84.

Hannenhalli, S., Putt, M.E., Gilmore, J.M., Wang, J., Parmacek, M.S., Epstein, J.A., Morrisey, E.E., Margulies, K.B., Cappola, T.A. Transcriptional genomics associates FOX transcription factors with human heart failure. Circulation. 2006 Sep 19;114(12):1269-76.

Luo, Y., High, F.A., Epstein, J.A., Radice, G.L. N-cadherin is required for neural crest remodeling of the cardiac outflow tract. Dev Biol. 2006 Nov 15;299(2):517-28.

High, F.A., Zhang, M., Proweller, A., Tu, L.L., Parmacek, M.S., Pear, W.S., Epstein, J.A. An essential role for Notch in neural crest during cardiovascular development and smooth muscle differentiation.J Clin Invest. 2007 February 1; 117(2): 353-363.

Trivedi, C.M., Luo, Y., Zhan, Y., Zhang, M., Zhu, W., Want, T., Floss, T., Goettlicher, M., Noppinger, P.R., Wurst, W., Ferrari, V.A., Abrams, C.S., Gruber, P.J., Epstein, J.A. Hdac2 regulates the cardiac hypertrophic response by modulating GSK3β activity. Nat Med.2007 Mar;13(3):324-331.

Vasyutina, E., Lenhard, D.C., Wende, H., Erdmann, B., Epstein, J.A., Birchmeier, C. RBP-J (Rbpsuh) is essential to maintain muscle progenitor cells and to generate satellite cells.Proc Natl Acad Sci U S A. 2007 Mar 13;104(11):4443-8.

 
 

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Reagents and Protocols

Protocols

Genotyping

Immunohistochemistry

Plasmids

General Use
Pax3-Related
c-ret related
ax7 related
Toto related
Lbx2 related
Plexin/Semaphorin related

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Contact

Jonathan Epstein
1154 BRB II/III
421 Curie Blvd
Philadelphia, PA 19104

Email: epsteinj@mail.med.upenn.edu
Phone: 215-898-8731
Fax: 215-898-9871
Lab Phone: 215-898-0252

Carolyn Phillips, Executive Assistant
Email: carolynp@mail.med.upenn.edu
Phone: 215-573-9306

Other Links:
Cell and Molecular Biology
Pennsylvania Muscle Institute

 

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Lab Members

Kurt Engleka | 215-898-0252 | kengleka@mail.med.upenn.edu

Jun Li | 215-573-7212 | Junli2@mail.med.upenn.edu

Fraz Ismat | 215-573-0634 | ismat@email.chop.edu

Jason Stoller | 215-573-7190 | stoller@email.chop.edu

Li Huang | 215-573-7212 | lihuang88@hotmail.com

Ying Zhang | 215-573-0634 | zhangy2@mail.med.upenn.edu

Frances High | 215-573-7190 | fhigh@mail.med.upenn.edu

Arun Padmanabhan | 215-573-0634 | apadmana@mail.med.upenn.edu

Chinmay Trivedi | 215-746-6324 | chinmay@mail.med.upenn.edu

Meilin Wu | 215-898-0252 | meilinwu@mail.med.upenn.edu

Junwang Xu | 215-573-7190 | junwang@mail.med.upenn.edu

Nicole Antonucci | 215-898-0252 | antonucb@mail.med.upenn.edu

Karl Degenhardt | 215-573-1220 | degenhardt@email.chop.edu

Qiaohong Wang | 215-898-0252 | qiaohong@mail.med.upenn.edu

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© 2006 The Trustees of the University of Pennsylvania