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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:

Singh N, Trivedi CM, Lu M, Mullican SE, Lazar MA, Epstein JA.Histone Deacetylase 3 Regulates Smooth Muscle Differentiation in Neural Crest Cells and Development of the Cardiac Outflow Tract. Circ Res. 2011 Sep 29. PMCID: PMC3225257

Zhu, C., Smith, T., McNulty, J., Rayla, A.L., Lakshmanan, A., Siekmann, A.F., Buffardi, M., Meng, X., Shin, J., Padmanabhan, A., Cifuentes, D., Giraldez, A.J., Look, A.T., Epstein, J.A., Lawson, N.D., and Wolfe, S.A.  Evaluation and application of modularly assembled zinc finger nucleases in zebrafish.  Development, 2011 Oct;138(20):4555-64. PMCID: PMC3177320

Takeda, N., Jain, R., LeBoeuf, M.R., Wang, Q., Lu, M.M., Epstein, J.A. Interconversion between intestinal stem cell populations in distinct niches.  Science. 2011 Dec 9;334(6061):1420-4.

Boudou, T., Legant, W.R., Mu, A., Borochin, M.A., Thavandiran, N., Radisic, M., Zandstra, P.W., Epstein, J.A., Margulies, K.B., Chen, C.S.  A Microfabricated platform to measure and manipulate the mechanics of engineered cardiac microtissues. Tissue Engineering, Tissue Eng Part A. 2012 Jan 4. PMCID:PMC3338105

Manderfield, L., High, FA, Engleka, KA, Liu, F, Rentschler, S, Epstein, JA (2011). "Notch activation of Jagged1 contributes to the assembly of the arterial wall: Jagged1 Is a direct Notch target." Circulation 2012 Jan 17;125(2):314-23. Epub 2011 Dec 6.  PMCID: PMC3260393

Banerjee, A., Trivedi, C.M., Damera, G., Jiang, M., Jester, W., Hoshi, T., Epstein, J.A., Panettieri, R.A.  Trichostatin a abrogates airway constriction, but not inflammation, in murine and human asthma models.  Am J Respir Cell Mol Biol. 2012 Feb;46(2):132-8. PMCID:PMC3297166

Zhang, H., Qiao, H., Frank, R.S., Huang, B., Propert, K.J., Margulies, S., Ferrari, V.A., Epstein, J.A., Zhou, R.  Spin Labeling-MRI Detects Increased Myocardial Blood Flow Post Endothelial Cell Transplantation in the Infarcted Heart.  Circ Cardiovasc Imaging. 2012 Feb 6. PMCID:PMC3322676

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. Circ Res. 2012 Mar 6. PMCID:PMC3355870

Katz. T.C., Singh, M.K., Degenhardt, K., Rivera-Feliciano, J., Johnson, R.L., Epstein, J.A., Tabin, C.J. Distinct compartments of the proepicardial organ give rise to coronary vascular endothelial cells.  Dev Cell. 2012 Mar 13;22(3):639-50. PMCID:PMC3306604

Singh MK, Epstein JA.  Epicardium-derived cardiac mesenchymal stem cells: expanding the outer limit of heart repair. Circ Res. 2012 Mar 30;110(7):904-6.

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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 Henry, 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

Cohen, Ashley

215-898-2800

ashcohen@mail.med.upenn.edu

Degenhardt, Karl

215-573-7548

degenhardt@email.chop.edu

DeGroh, Eric

215-573-2623

edegroh@mail.med.upenn.edu

Engleka, Kurt

215-898-0252

kengleka@mail.med.upenn.edu

Gupta, Mudit

215-573-7212

guptam@mail.med.upenn.edu

Li, Deqiang

215-573-2598

degli@mail.med.upenn.edu

Li, Jun

215-573-7212

junli2@mail.med.upenn.edu

Liu, Feiyan

215-573-7548

feiyan@mail.med.upenn.edu

Manderfield, Lauren

215-898-0252

lauman@mail.med.upenn.edu

Padmanabhan, Arun

215-573-7215

apadmana@mail.med.upenn.edu

Rentschler, Stacey

215-573-3011

stacey.rentschler@uphs.upenn.edu

Singh, Manvendra

215-573-3860

masingh@mail.med.upenn.edu

Singh, Nikhil

215-573-7215

nikhil2@mail.med.upenn.edu

Takeda, Norifumi

215-573-7548

notakeda@mail.med.upenn.edu

Wang, Qiaohong

215-898-2800

qiaohong@mail.med.upenn.edu

 

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