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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:

High, F.A., Lu, M.M., Pear, W.S.,Loomes, K.M., Kaestner, K.H., Epstein, J.A. Endothelial expression of the Notch ligand Jagged1 is required for vascular smooth muscle development . Proc Natl Acad Sci. U S A. 2008 Feb 12;105(6):1955-9.

Huang, J., Cheng, L., Li, J., Chen, M., Zhou, D., Lu, M.M., Proweller, A., Epstein, J.A., Parmacek, M.S. Myocardin regulates expression of contractile genes in smooth muscle cells and is required for closure of the ductus arteriosus in mice. J Clin Invest. 2008 Feb; 118(2):515-25.

Hori, K., Cholewa-Waclaw, J., Nakada, Y., Glasgow, S.M., Masui, T., Henke, R.M., Wildner, H., Martarelli, B., Beres, T.M., Pear, W., Epstein, J.A., Magnuson, M.A., MacDonald, R.J., Birchmeier, C., Johnson, J.E. A Non-classical bHLH-Rbpj Transcription Factor Complex is Required for Specification of GABAergic Neurons Independent of Notch Signaling. Genes & Dev. 2008 Jan 15:22(2):166-78.

Stoller, J.Z., Degenhardt, K.R., Huang, L., Zhou, D., Lu, M.M., Epstein, J.A.  Cre reporter mouse expressing a nuclear localized fusion of GFP and b-glactosidase reveal new derivatives of Pax3-expressing precursors.  Genesis. 2008 Apr 46(4):200-4.

De Toni, A., Zbinden, M., Epstein, J.A., Ruiz i Altaba, A., Prochiantz, A., Caille, I.  Regulation of survival in adult hippocampal and glioblastoma stem cell lineages by the homeodomain-only protein HOP.  Neural Development. 2008 May 28;3:13.

Tan, C.C., Sindhu, K.V., Li, S.D., Nishio, H., Stoller, J.Z., Oishi, K., Puttreddy, S., Lee, T.J., Epstein, J.A., Walsh, M.J., Gelb, B.D.  Transcription factor Ap2d associates with Ash21 and ALR, a trithorax family histone methyltransferase, to activate Hoxc8 transcription.  Proc Natl Acad Sci. U S A, 2008 May 27;105(21):7472-7.

Wu, M., Li, J., Engleka, K.A., Zhou, B., Lu, M. M., Plotkin, J., Epstein, J.A. Persistent expression of Pax3 in the neural crest causes cleft palate and defective osteogenesis in mice. J Clin Invest. 2008 Jun 11; 118(6):2076-87.

Granger A., Abdullah I., Huebner F., Wang T., Stout A., Huebner T., Epstein J.A., Gruber P.J. Histone deacetylase inhibition reduces myocardial ischemia-reperfusion injury in mice. FASEBJ. 2008 Jul 7.

Trivedi, C.M., Lu, M.M., Wang, Q., Epstein, J.A. Transgenic over-expression of Hdac3 in the heart produces increased postnatal cardiac myocyte proliferation but does not induce hypertrophy. J Biol Chem. 2008 Jul 14. [Epub ahead of print]

Lagha, M., Kormish, J.D., Rocancourt, D., Manceau, M., Epstein, J.A., Zaret, K.S., Relaix, F., Buckingham, M.E.. Pax3 regulation of FGF signaling affects the progression of embryonic progenitor cells into the myogenic program. Genes Dev. 2008 Jul 1;22(13):1828-37.

 
 

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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

Ying Zhang | 215-573-0634 | zhangy2@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

Stacey Rentschler | 215-573-3011 | stacey.rentschler@uphs.upenn.edu

Rajan Jain | 215-573-3011 | rajan.jain@uphs.upenn.edu

Wenting Zhu | 215-573-7212 | zwenting@sas.upenn.edu

Manvendra Singh | 215-573-3860 | masingh@mail.med.upenn.edu

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