Research 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.
Rotation Projects for 2009-2010
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
Lab personnel:
Alex Brown (Graduate Student)
Diane Dolson (Research Specialist)
Staci Rackowiecki (Research Specialist)
Solsire Zevallos (Graduate Student)
Yao Yao, Ph.D. (Postdoctoral Fellow)
Li Zhao, Ph.D. (Postdoctoral Fellow)
Selected Publications
Douglas J. Epstein: Cis-regulatory mutations in human disease. Briefings in Functional Genomics and Proteomics doi:10.1093/bfgp/elp021, 2009.
Jeong, Y., Coluccio Leskow, F., Yocum, A., El-Jaick, K., Roessler, E., Muenke, M., Yocum, A., Dubourg, C., Li, X., Geng, X., Oliver, G. and Epstein, D.J.: Regulation of a remote Sonic hedgehog forebrain enhancer by the Six3 homeoprotein. Nature Genetics 40: 1348-1353, 2008.
Geng, X., Speirs, C., Lagutin, O., Inbal, A., Liu, W., Solnica-Krezel., L., Jeong, Y., Epstein, D.J. and Oliver, G. : Haploinsufficiency of Six3 fails to activate Sonic hedgehog expression in the ventral forebrain and causes holoprosencephaly. Developmental Cell 15: 236-247, 2008.
Torban, E., Patenaude, A., Leclerc, S., Rakowiecki, S., Gauthier, S., Andelfinger, G., Epstein D.J. and Gros, P.: Genetic interaction between members of the Vangl family causes neural tube defects in mice. PNAS 105: 3449-54, 2008.
Bok, J., Dolson, D.K., Hill, P., Ruther, U., Epstein, D.J. and Wu, D.K. : Opposing gradients of Gli repressor and activators mediate Shh signaling along the dorsoventral axis of the inner ear. Development 134: 1713-1722, 2007.
Pachikara, A., Dolson, D.K., Martinu, L., Riccomagno, M.M., Jeong, Y. and
Epstein, D.J.
: Activation of Class I transcription factors by low level Sonic hedgehog signaling is mediated by Gli2-dependent and independent mechanisms. Developmental Biology 305: 52-62, 2007.
Lei, Q., Jeong, Y., Misra, K., Li, S., Zelman, A.K., Epstein, D.J. and Matise, M.P.: Wnt signaling inhibitors regulate the transcriptional response to morphogenetic Shh-Gli signaling in the neural tube. Developmental Cell 11: 325-337, 2006.
Jeong, Y., El-Jaick, K., Roessler, E., Muenke, M., and Epstein, D.J.: A functional screen for Sonic hedgehog regulatory elements across a 1 Mb interval identifies long range ventral forebrain enhancers. Development 133: 761-772, 2006.
Riccomagno, M.M., Takada, S. and Epstein, D.J. : Wnt dependent regulation of inner ear morphogenesis is balanced by the opposing and supporting roles of Shh. Genes and Development 19: 1612-23, 2005.
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Last updated: 10/06/2009
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