Penn Medicine

Jonathan A. Epstein, M.D.

Department of Medicine, Institute for Human Gene Therapy

Contact Information

Department of Medicine
Hospital of the University of Pennsylvania
809 Stellar Chance Labs
422 Curie Blvd.
Philadelphia, PA 19104-6086
Phone: (215) 898-8731
Fax: (215) 573-2094
Position: Assistant Professor


My research interests focus on the molecular mechanisms of cardiac and muscle development and function. Our work has focused on the transcriptional mechanisms of members of the Pax family of transcription factors that play critical roles in the determination and development of multiple organs and tissues. Pax3 is required for proper heart and muscle development in the mouse, and mutations in PAX3 cause deafness and Waardenburg syndrome in humans. Translocations involving PAX3 cause tumors of muscle. By studying embryonic development, we have identified transcriptional targets of Pax3 and PAX3/FKHR (the oncogenic product of chromosomal translocation) that are critical for development and may promote tumor progression in adults. These include the c-met oncogene and the PDGFalpha receptor. These examples emphasize the potential impact of the study of developmental processes on the understanding of adult human disease.

Other projects involve the use of transgenic technologies in the mouse to correct the congenital heart disorder of Splotch mutant mice, thus demonstrating that Pax3 expression regulated by a 1.9Kb promoter fragment is sufficient to direct outflow tract septation. In addition, we have shown that Pax3 regulates an apoptotic pathway and represses Pax7, a closely related family member. We are also interested in the study of cardiac hypertrophy, using the mouse embryonic heart as a model. We have identified known and novel genes emerging during mid-gestation at the time when contractile function becomes critical. Future studies will involve the analysis of some of these unknown genes through gene targeting studies in the mouse. In addition, we have analyzed the effect of inactivation of the neurofibromatosis gene on cardiac development and have demonstrated that Nf1 is required for the proper regulation of the Ras pathway during valve formation, thus implicating Ras for the first time in this aspect of cardiac development. We believe that analysis of the role of Nf1 in heart formation may serve as a model for the further understanding of the role of Nf1 as a tumor suppressor gene.

Representative Publications

  1. Epstein, J., Shapiro, D., Cheng, J., Lam, P., and Maas, R. Pax3 modulates expression of the c-MET receptor during limb muscle development. Proc. Natl. Acad. Sci. USA, 1996; 93:4213-4218.
  2. Epstein, J. Pax3, neural crest and cardiac development. Trends in Cardiovascular Medicine, 1996; 6:255-261.
  3. Epstein, J.A., Song, B., Lakkis, M., Wang, C. The tumor specific PAX3-FKHR transcription factor, but not Pax3, activates the platelet-derived growth factor alpha receptor. Mol. Cell. Biol., 1998; 18:4118-4130.
  4. St. John Sutton, M. and Epstein, J.A. Hypertrophic cardiomyopathy -- beyond the sarcomere. (editorial) New England Journal of Medicine, 1998; 338:1303-1304.
  5. Lakkis, M.M. and Epstein, J.A. Neurofibromin modulation of ras activity is required for normal endocardial-mesenchymal transformation in the developing heart. Development, in press.
  6. Epstein, J.A. Pax3 gene mutations and heart morphogenesis. Vol. 2, Developmental Biology Protocols. In: Tuan, R.S. and Lo, C.W. eds. Methods in Molecular Biology, Totowa, N.J., Humana Press, Inc., in press.
  7. Borycki, A.G., Li, J., Emerson, C.P.Jr., Epstein, J.A. Pax3 functions in somite cell survival and regulates pax7. Submitted.


Pennsylvania Muscle Institute
Perelman School of Medicine University of Pennsylvania
Director: E. Michael Ostap, Ph.D.

700A Clinical Research Building Philadelphia, PA 19104-6085 Phone: (215) 573-9758 Fax: (215) 898-2653