Posted February 02, 2010
The Notch signaling pathway controls cell fate throughout development in a variety of organisms, from fruit flies to humans. The pathway is crucial for the growth and maturation of numerous systems and organs, including the brain. However, evidence is mounting to suggest that if this pathway goes awry, it contributes to or causes brain tumors, prion disease, multiple sclerosis, and other diseases.
At an April 25, 2006, Academy meeting, researchers discussed a tool for exploring the role of Notch in CNS and kidney development, efforts to treat tumors using Notch inhibitors, the role of Notch signaling in prion disease, and the role of Notch in the maturation of immune system cells.
Use the tabs above to find a meeting report and multimedia from this event.
The European Molecular Biology Organization (EMBO)
A professional organization that holds conferences, publishes journals, and disseminates information about molecular biology.
The Federation of American Societies for Experimental Biology (FASEB)
FASEB advances biological science through collaborative advocacy for research policies that promote scientific progress and education and lead to improvements in human health.
The Reactome Project
The Project is a collaboration among Cold Spring Harbor Laboratory, The European Bioinformatics Institute, and The Gene Ontology Consortium to develop a curated resource of core pathways and reactions in human biology. Visit the Notch Signaling Pathway page for information on the molecules involved.
Beckerman, M. 2005. Molecular and cellular signaling. Springer, New York.
Bongarzone, E. R., N. Gaiano & G. Consalez, Eds. 2006. Notch signaling and nervous system development. Karger, Basel.
Israel, A., B. de Strooper, F. Checler & Y. Christen, Eds. 2002. Notch from Neurodevelopment to Neurodegeneration: Keeping the Fate. Springer, New York.
Notch Signaling: How Do Vertebrates Use Their Four Notch Genes?
Cheng, H. T. & R. Kopan. 2005. The role of Notch signaling in specification of podocyte and proximal tubules within the developing mouse kidney. Kidney Int. 68: 1951-1952.
Huppert, S. S., A. Le, E. H. Schroeter, et al. 2000. Embryonic lethality in mice homozygous for a processing-deficient allele of Notch1. Nature 405: 966-970. Erratum in: Nature 2000 408: 616.
Koo, E. H. & R. Kopan. 2004. Potential role of presenilin-regulated signaling pathways in sporadic neurodegeneration. Nat. Med. 10 Suppl: S26-33.
Kopan, R. & A. Goate. 2000. A common enzyme connects notch signaling and Alzheimer's disease. Genes Dev. 14: 2799-2806. FULL TEXT
Kopan, R. & A. Goate. 2002. Aph-2/nicastrin: an essential component of gamma-secretase and regulator of Notch signaling and presenilin localization. Neuron 33: 321-324.
Ong, C. T., H. T. Cheng, L. W. Chang, et al. 2006. Target selectivity of vertebrate notch proteins. Collaboration between discrete domains and CSL-binding site architecture determines activation probability. J. Biol. Chem. 281: 5106-5119.
Pan, Y., M. H. Lin, X. Tian, et al. 2004. gamma-secretase functions through Notch signaling to maintain skin appendages but is not required for their patterning or initial morphogenesis. Dev. Cell. 7: 731-743.
Selkoe, D. & R. Kopan. 2003. Notch and presenilin: regulated intramembrane proteolysis links development and degeneration. Annu. Rev. Neurosci. 26: 565-597.
Wolfe, M. S. & R. Kopan. 2004. Intramembrane proteolysis: theme and variations. Science 305: 1119-1123.
Yang, X., T. Tomita, M. Wines-Samuelson, et al. 2006. Notch1 signaling influences v2 interneuron and motor neuron development in the spinal cord. Dev. Neurosci. 28: 102-117.
The Role of Notch Signaling and the Initiation and Growth of Brain Tumors
Dang, L., X. Fan, A. Chaudhry, et al. 2006. Notch3 signaling initiates choroid plexus tumor formation. Oncogene 25: 487-491.
Fan, X., I. Mikolaenko, I. Elhassan, et al. 2004. Notch1 and notch2 have opposite effects on embryonal brain tumor growth. Cancer Res. 64: 7787-7793. FULL TEXT
Purow, B. W., R. M. Haque, M. W. Noel, et al. 2005. Expression of Notch-1 and its ligands, Delta-like-1 and Jagged-1, is critical for glioma cell survival and proliferation. Cancer Res. 65: 2353-2363. FULL TEXT
Solecki, D. J., X. L. Liu, T. Tomoda, et al. 2001. Activated Notch2 signaling inhibits differentiation of cerebellar granule neuron precursors by maintaining proliferation. Neuron 31: 557â€“568.
Notch Signaling Pathways in Prion Disease
Ishikura, N., J. L. Clever, E. Bouzamondo-Bernstein, et al. 2005. Notch-1 activation and dendritic atrophy in prion disease. Proc. Natl. Acad. Sci. USA 102: 886-891. FULL TEXT
Regulation of Inflammatory Responses by Notch Signaling
Minter, L. M., D. M. Turley, P. Das, et al. 2005. Inhibitors of gamma-secretase block in vivo and in vitro T helper type 1 polarization by preventing Notch upregulation of Tbx21. Nat. Immunol. 6: 680-688.
Nickoloff, B. J., B. A. Osborne, & L. Miele. 2003. Notch signaling as a therapeutic target in cancer: a new approach to the development of cell fate modifying agents. Oncogene 22: 6598-6608.
Palaga, T., L. Miele, T. E. Golde & B. A. Osborne. 2003. TCR-mediated Notch signaling regulates proliferation and IFN-gamma production in peripheral T cells. J. Immunol. 171: 3019-3024. FULL TEXT
Shin, H. M., L. M. Minter, O. H. Cho, et al. 2006. Notch1 augments NF-kappaB activity by facilitating its nuclear retention. EMBO J. 25: 129-138.
Raphael Kopan, PhD
Raphael Kopan is professor of molecular biology and pharmacology at Washington University. He is also professor of medicine in the Division of Dermatology. His research team is investigating the Notch signal transduction pathway, which provides developing tissues with a short-range communication channel for mediating cell-cell interactions. A second focus in the lab is intramembrane proteolysis mediated by a presenilin-containing enzyme, γ-secretase.
After receiving his PhD in molecular genetics and cell biology from the University of Chicago, Kopan completed his postdoctoral training at the Fred Hutchinson Cancer Research Center and went on to join the faculty of Washington University. Kopan is the recipient of several awards and fellowships, including the Leukemia Society of America fellowship and the Marcus Singer Medal for furthering research in regeneration and developmental biology. He is the associate editor of Developmental Cell and serves on several advisory boards and committees, including the National Institutes of Health, the National Science Foundation, and Sigma Scientific Advisory Board.
Charles G. Eberhart, MD, PhD
Charles Eberhart is assistant professor of pathology and oncology at Johns Hopkins University. His laboratory studies the molecular genetics of medulloblastoma, glioblastoma, and other brain tumors. The focus is on the Notch and Hedgehog pathways, which play a key role in both normal brain development and neoplasia. Eberhart is currently analyzing the effects of Notch and Hedgehog pathway blockade on the growth and viability of brain tumors. He is also investigating the basis of the sometimes antagonistic effects of various Notch receptors in medulloblastoma and the way in which such effects relate to the receptors' roles in neural stem-cell proliferation and differentiation. Finally, he is examining the role of c-Myc in the anaplastic progression of medulloblastoma.
Eberhart received his doctorate as well as his medical degree from the University of Texas Southwestern Medical School. He completed his postgraduate training as a resident in anatomic pathology and as a fellow in neuropathology at the Johns Hopkins Hospital.
Stephen J. DeArmond, MD, PhD
Stephen DeArmond earned his PhD and MD at the Medical College of Pennsylvania, and completed two years of internship and residency training in anatomic pathology and three years of neuropathology fellowship training at Stanford University Medical Center. Following three years of research of glial fibrillary acidic protein in Lawrence Eng's laboratory at the Palo Alto Veteran's Administration Medical Center and a junior faculty appointment at Stanford, in 1983 he was recruited to the Pathology Department at the University of California, San Francisco.
After arriving at UCSF, DeArmond founded the Neuropathology Research Laboratory, which focuses on the cell biological and molecular mechanisms of neurodegeneration in prion diseases. He has studied the prion PrPSc extensively, showing that amyloid plaques in Creutzfeldt-Jakob disease are composed of PrPSc and that accumulation of non-amyloid PrPSc in the brain is the cause of early synaptic dysfunction and degeneration, and of late occurring nerve cell death. He also found a direct correlation between synaptic PrPSc accumulation and activation of the Notch1 intracellular domain (NICD). This discovery holds potential that prevention of Notch1 activation by pharmaceutical agents might prevent progressive cognitive decline in prion diseases and possibly even in other dementing disorders.
Barbara A. Osborne, PhD
Barbara Osborne is professor in the Veterinary and Animal Sciences Department at the University of Massachusetts. She is also cofounder, owner, and senior consultant of Hematech, LLC. Her laboratory studies two aspects of lymphocyte development and diversification. One area of active investigation is the elucidation of the molecular events required for the induction of apoptosis in the mouse thymus. The other project focuses on B cell development and mechanisms of generation of immunoglobulin diversity in cattle.
Osborne received her PhD in genetics from Stanford University. She worked as the Damon Runyon-Walter Winchell Postdoctoral Fellow at the National Institutes of Health and joined the faculty of the University of Massachusetts as a research associate. Osborne is a member of the Whitehead Institute board of associates and has serves as chair of the board of scientific counselors of the National Institute of Allergy and Infectious Diseases and the National Institutes of Health. She is also senior editor of Cell Death & Differentiation and serves on the editorial board of the Journal of Immunology. In addition to these responsibilities, Osborne is a member of the Federation of American Societies for Experimental Biology and the American Association of Immunologists finance committees.
Catherine Zandonella is a science writer based in New York City, covering such topics as environmental science, public health, and applied technology. She has a master's degree in public health from the University of California, Berkeley. Zandonella has written for a number of publications, including New Scientist, The Scientist, and Nature.