The Notch signaling pathway defines a cell interaction mechanism, which defines one of the cornerstones of the signaling backbone in metazoans. The essential role Notch signals play in the early development of the nervous system, has been recognized fifty years ago and it has become clear that Notch signals are essential in almost all aspects of neural development starting from the differentiation of neural stem cells to the elaboration of neuritis in postmitotic neurons. Numerous analyses in vertebrate and invertebrate model systems as well as in humans over the years has, however, established that the action of the Notch pathway is far broader than the confines of the nervous system and that it is used throughout development to couple the fate choice of a particular cell to the fate of the next door neighbor ultimately affecting proliferation, apoptotic and differentiation events. The overall goal of this proposal is to dissect the molecular elements of Notch signaling and gain insight into the complexity and the degree to which Notch signaling response is tissue specific. We will use both classic as well as genomic approaches to achieve our goals.
Four specific aims are proposed a) In an attempt to gain insight into the function and biology of mastermind, a nuclear effector of Notch signals, we propose to carry out a classic genetic screen for second site modifiers of mastermind phenotypes as well as examine some of the biochemical properties of Mastermind. b) We propose a two-hybrid approach in an attempt to construct a protein interaction map involving most of the known elements of the Notch pathway c) We will examine the transcriptional complexity of the Notch signal response, in order to study the tissue specificity, signal integration with other pathways and quantitative aspects of Notch signals, d) Finally we propose molecular genome-wide screens for modifiers of Notch activity using an RNAi approach in tissue culture cells. These studies will be complemented by chemical screens for Notch signal modifiers.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Method to Extend Research in Time (MERIT) Award (R37)
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Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
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Leblanc, Gabrielle G
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Massachusetts General Hospital
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Hori, Kazuya; Sen, Anindya; Artavanis-Tsakonas, Spyros (2014) Genetic circuitry modulating notch signals through endosomal trafficking. Methods Enzymol 534:283-99
Hori, Kazuya; Sen, Anindya; Artavanis-Tsakonas, Spyros (2013) Notch signaling at a glance. J Cell Sci 126:2135-40
Arboleda-Velasquez, Joseph F; Manent, Jan; Lee, Jeong Hyun et al. (2011) Hypomorphic Notch 3 alleles link Notch signaling to ischemic cerebral small-vessel disease. Proc Natl Acad Sci U S A 108:E128-35
Sun, Youping; Klauzinska, Malgorzata; Lake, Robert J et al. (2011) Trp53 regulates Notch 4 signaling through Mdm2. J Cell Sci 124:1067-76
Fre, Silvia; Hannezo, Edouard; Sale, Sanja et al. (2011) Notch lineages and activity in intestinal stem cells determined by a new set of knock-in mice. PLoS One 6:e25785
Hori, Kazuya; Sen, Anindya; Kirchhausen, Tom et al. (2011) Synergy between the ESCRT-III complex and Deltex defines a ligand-independent Notch signal. J Cell Biol 195:1005-15
Mazzone, Marco; Selfors, Laura M; Albeck, John et al. (2010) Dose-dependent induction of distinct phenotypic responses to Notch pathway activation in mammary epithelial cells. Proc Natl Acad Sci U S A 107:5012-7
Mourikis, Philippos; Lake, Robert J; Firnhaber, Christopher B et al. (2010) Modifiers of notch transcriptional activity identified by genome-wide RNAi. BMC Dev Biol 10:107
Kelly, Deborah F; Lake, Robert J; Middelkoop, Teije C et al. (2010) Molecular structure and dimeric organization of the Notch extracellular domain as revealed by electron microscopy. PLoS One 5:e10532
Fre, Silvia; Pallavi, S K; Huyghe, Mathilde et al. (2009) Notch and Wnt signals cooperatively control cell proliferation and tumorigenesis in the intestine. Proc Natl Acad Sci U S A 106:6309-14

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