Douglas J. Epstein, Ph.D.
415 Curie Boulevard
Philadelphia, PA 19104
Fax: 215 573-5892
McGill University, 1986.
McGill University, 1989.
McGill University, 1993.
Description of Research ExpertiseResearch Interests
Regulation of Sonic hedgehog signaling in development and disease
Key words: mouse, development, signal transduction, transcription, central nervous system, hearing, cancer, genetics.
Description of Research
The secreted protein, Sonic hedgehog (Shh), plays an integral role in forming the ventral midline of the vertebrate central nervous system (CNS). In the absence of Shh function, ventral midline development is perturbed resulting in holoprosencephaly (HPE), a structural malformation of the brain, as well as neuronal patterning and path finding defects. Central to the understanding of ventral neural tube development is how Shh transcription is regulated in the CNS. Research in my laboratory employs genetic, genomic and biochemical approaches to uncover the cis and trans acting determinants of Shh expression in the mouse CNS. An understanding of how Shh expression is initiated in the ventral forebrain may provide insight into additional causes of holoprosencephaly.
Figure 1: Shh expression in the CNS is controlled by short and long range acting enhancers.
A second focus of research in my laboratory addresses the genetic programs underlying inner ear morphogenesis. The principal components for hearing (cochlea) and balance (vestibulum) are formed from ventral and dorsal outgrowths, respectively, of a common bilateral structure, the otocyst. Organization of the inner ear into auditory and vestibular components is established early in development and is heavily influenced by surrounding tissues. The proximity of the otocyst to the hindbrain suggested that extracellular signals that pattern the CNS might also polarize the otic epithelium along its dorsoventral axis. Experiments in my laboratory address the specific contributions of Shh and Wnt signaling pathways in promoting cochlear and vestibular development, respectively.
Figure 2: Morphology of the developing inner ear. Hearing and balance are coordinated by stimulation of vestibular (red) and auditory (green, yellow) hair cells in the semicircular canals and cochlea, respectively.
1. Screen for novel regulators of Shh transcription in the mouse central nervous system
2. Trace the lineage of Shh responsive cells in the hypothalamus
3. Identify and characterize novel genes regulated by Shh and Wnt signaling in the inner ear
Alex Rohacek (Graduate Student)
Tanya Corman (Graduate Student)
Staci Rakowiecki (Research Specialist)
Victor Muthu, Ph.D. (Postdoctoral Fellow)
Yao Yao, Ph.D. (Postdoctoral Fellow)
Selected PublicationsRakowiecki, S. and Epstein, D.J. : Divergent roles for Wnt/β-catenin signaling in epithelial maintenance and breakdown during semicircular canal formation. Development 140: 1730-9, 2013.
Trowe, M-O., Zhao, L., Weiss, A-C., Christoffels, V., Epstein, D.J.* and Kispert, A.* : Inhibition of Sox2-dependent activation of Shh in the ventral diencephalon by Tbx3 is required for the formation of the neurohypophysis Development 140: 2299-2309, 2013 Notes: *corresponding authors.
Zhao, L., Zevallos, S., Rizzoti, K., Jeong, Y., Lovell-Badge, R. and Epstein, D.J.: Disruption of SoxB1 dependent Sonic hedgehog expression in the hypothalamus causes Septo-Optic Dysplasia. Developmental Cell 22: 585-596, 2012.
Lee, B., Rizzoti, K., Kwon, D.S., Kim, S-Y., Oh, S., Epstein, D.J., Yoon, J. Baek, K. and Jeong, Y. : Direct transcriptional regulation of Six6 is controlled by SoxB1 binding to a remote forebrain enhancer. Developmental Biology 366: 393-403, 2012.
Brown, A. S., Epstein, D. J.: Otic ablation of smoothened reveals direct and indirect requirements for Hedgehog signaling in inner ear development. Development 138(18): 3967-76, 2011.
Jeong, Y., Dolson, D. K., Waclaw, R. R., Matise, M. P., Sussel, L., Campbell, K., Kaestner, K. H., Epstein, D. J.: Spatial and temporal requirements for sonic hedgehog in the regulation of thalamic interneuron identity. Development 138(3): 531-41, 2011.
Madison, B. B., McKenna, L. B., Dolson, D., Epstein, D. J., Kaestner, K. H.: FoxF1 and FoxL1 link hedgehog signaling and the control of epithelial proliferation in the developing stomach and intestine. The Journal of Biological Chemistry 284(9): 5936-44, 2009.
Geng, X., Speirs, C., Lagutin, O., Inbal, A., Liu, W., Solnica-Krezel, L., Jeong, Y., Epstein, D. J., Oliver, G.: Haploinsufficiency of Six3 fails to activate Sonic hedgehog expression in the ventral forebrain and causes holoprosencephaly. Developmental Cell 15(2): 236-47, 2008.
Torban, E., Patenaude, A. M., Leclerc, S., Rakowiecki, S., Gauthier, S., Andelfinger, G., Epstein, D. J., Gros, P.: Genetic interaction between members of the Vangl family causes neural tube defects in mice. Proceedings of the National Academy of Sciences of the United States of America 105(9): 3449-54, 2008.
Jeong, Y., Leskow, F. C., El-Jaick, K., Roessler, E., Muenke, M., Yocum, A., Dubourg, C., Li, X., Geng, X., Oliver, G., Epstein, D. J.: Regulation of a remote Shh forebrain enhancer by the Six3 homeoprotein. Nature Genetics 40(11): 1348-53, 2008.