department of developmental biology
Professor
Co-director, Washington University High Throughput Core http://molecool.wustl.edu/RB/RBHome.html
Department of Developmental Biology
Department of Medicine
Developmental Biology Program
Molecular Cell Biology Program
Neurosciences ProgramResearch Interests
When thinking about the origins of cell-type or species diversity, a central realization is that only 8 signaling pathways (Notch, Wnt, HH, TGF, RTK, GPCR, NFkB and Jak/Stat) allow near infinite number of variations. My lab demonstrated that Notch signaling is propagated through release of its intracellular domain, which acts as a nuclear transcription factor. Notch mediates short-range signals leading to inhibition or promotion of a cellular function in cells that experience Notch activation. Our lab continues to focus on Notch signaling as our lead into attaining a functional understanding of diversity. Our long-term goal is to contribute to efforts aimed at organ formation in vitro from adult or embryonic stem cells. Our efforts are split into two broad focus areas. Students and Fellows joining the lab will be participating in these efforts or craft new directions based on their interests and ours.
We are testing the integration of Notch with additional signaling pathways via high throughput screening of siRNA and chemical libraries in assays our lab has developed. Using genetic engineering, we are manipulating mouse embryos to create new Notch alleles with which to address critical questions regarding redundancy of Notch paralogs and decipher the circuit logic of Notch signaling in mammalian organogenesis. Our main efforts are aimed at comparing and contrasting the activity of Notch signaling in development, maintenance and disease of two organs - the skin and the metanephric kidney. The epidermis and hair follicle are both model systems for the study of cell diversity at the tissue level; the vertebrate skin as a whole combines many advantages for our studies. It differentiate properly only as a result of mesenchymal-epithelial interactions and responds to hormonal signals. Many known signaling pathways are active in skin differentiation and most importantly, the skin can tolerate disruption. The Kidney offers many of the same advantages regarding integration of signals. It is a glandular-type model involving mesenchymal-epithelial transition and its strength include well-developed organ-culture techniques. Our lab is currently attempting to perfect siRNA, virus and cDNA delivery into cultured kidney anlagen.
A second focus of my lab is to understand the molecular basis of intramembrane proteolysis. We use biochemical, genetic and high throughput approaches to understand substrate selection and discrimination and the use of RIP in development and disease.Kopan Biosketch
Education
- 1978-1981, B.S. in Biology, Tel-Aviv University,Tel-Aviv, Israel.
- 1981-1984, M.S. in the Department of Zoology, Tel-Aviv University Tel-Aviv, Israel. Under supervision of Dr. Michael Ovadia. Graduated Summa Cum Laude.
- 1985-1989, Ph.D. in the Department of Molecular Genetics and Cell Biology at the University of Chicago. Thesis Advisor Elaine Fuchs.
- 1990-1994, Postdoctoral Training with Dr. Harold Weintraub, Fred Hutchinson Cancer Research Center, Seattle.
Academic Positions/Employment:
- 1981-1984, Teaching Assistant in the Department of Zoology, Tel-Aviv University, Israel. Graduate courses in the Embryology, Comparative Anatomy and Entomology Labs.
- 1987-1988, Teaching Assistant at the University of Chicago, Chicago, Illinois, (Graduate Courses in Developmental and Molecular Biology).
- 1994-1999, Assistant Professor of Medicine (Dermatology); Molecular Biology and Pharmacology.
- 1999-Present, Associate Professor of Molecular Biology and Pharmacology; Medicine (Dermatology).
- Co-director, Washington University High Throughput Core
http://molecool.wustl.edu/RB/RBHome.htmlSelected Publications
Hadland BK, Manley N, Su D, Longmore GD, Moore CL, Wolfe MS, Schroeterl EH, and Kopan, R: gamma-Secretase inhibitors repress thymocyte development. PNAS, 2001, 98, 7487-7491..Huppert S, Le A, Schroeter EH, Mumm SJ, Saxena MT, Milner L, and Kopan R: Embryonic lethality in mice homozygous for a processing deficient Notch 1 allele. Nature, 2000, 405, 966-970.
Lin M-H, Leimeister C, Gessler M, and Kopan R: Activation of the Notch pathway in the hair cortex leads to aberrant differentiation of the adjacent hair-shaft layers. Development, 2000 127, 2421-2432.
Mumm JS, Schroeter EH, Saxena MT, Griesemer A, Tian X, Pan DJ, Ray WJ, and Kopan R: A ligand-induced extracellular cleavage regulates gamma-secretase-like proteolytic activation of Notch 1. Mol. Cell 2000, 5, 197-206.
Ray WJ, Yao M, Mumm J, Schroeter EH, Wolfe M, Selkoe DJ, Kopan R, and Goate AM: Cell surface presenilin-1 participates in the gamma-secretase-like proteolysis of Notch. J. Biol. Chem. 1999, 274:36801-36807.
Steiner H, Duff K, Capell A, Romig H, Grim MG, Lincoln S, Hardy J, Yu X, Picciano M, Fechteler K, Citron M, Kopan R, Pesold B, Keck S, Baader M, Tomita T, Iwatsubo T, Baumeister R, and Haass C: A loss of function mutation of presenilin-2 interferes with amyloid b-peptide production and notch signaling. J. Biol. Chem. 1999; 274:28669-28673.
Wittenbergern T, Steinbach OC, Authaler A, Kopan R, and Rupp R: MyoD Stimulates Delta-1 Transcription and Triggers Notch Signaling in the Xenopus Gastrula. EMBO Journal 1999;18:1915-1922.
De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K, Mumm JS, Schroeter EH, Schrijvers V, Wolfe MS, Ray WJ, Goate A, and Kopan R: A Presenilin-1-dependent, gamma-secretase-like protease mediates release of Notch intracellular domain. Nature 1999; 398:518-522.
Ray WJ, Yao M, Zhang W, Wu JY, Mumm J, Kopan R, and Goate AM: Presenilin-1 and notch1 physically interact in mammalian cells. PNAS 1999; 96:3263-3268.
Schroeter EH, Kisslinger JA and Kopan R: Notch 1 signaling requires ligand-induced proteolytic release of intracellular domain. Nature 1998; 393:382-386. See the appendix to this manuscript: http://molecool.wustl.edu/Kopan/appA.htm.
Selected ReviewsKopan R and Turner DL: The Notch pathway: democracy and aristocracy in the selection of cell fate.ĘCurrent Opinion in Neurobiology 1996;6:594-601.
Kopan R and Cagan, R.: Notch at the cutting edge (comment). Trends in Genetics, 1997:13;465-467.
Good Things Must Come to an End: How Is Notch Signaling Turned off? Kopan R. See the manuscript at: http://www.stke.org/cgi/content/full/OC_sigtrans;1999/9/pe1.
Mumm JS, and Kopan R: Notch Signaling: From the outside in. Developmental Biology, 2000: 228,151-165. 8. See figures and legends from the manuscript: http://molecool.wustl.edu/Kopan/outside-in.htm.
Kopan R and Goate A: A common enzyme connects Notch signaling with Alzheimer disease. Genes and Development. 2000; 14: 2799-2806. See figures from the manuscript: http://molecool.wustl.edu/Kopan/comenz02.htm.
Contact Information
Raphael Kopan
Department of Developmental Biology
Washington University School of Medicine
Campus Box 8103
660 South Euclid Avenue
St. Louis, MO 63110
(314) 747-5520
kopan@wustl.eduLaboratory Website
Developmental Biology Program Website