Neurogenesis in D. melanogaster is under the control of a small group of unlinked genes, collectively known as the neurogenic loci. Mutations in any one of these six loci result in qualitatively similar phenotypes: cell destined to become precursors of the epidermis """"""""switch"""""""" fate and become neuroblasts. Through the molecular analysis of the Notch locus, which is the best characterized neurogenic locus, we have gained insight into the biochemical nature of the gene product and its mode of action during development. We have demonstrated that Notch codes for a large transmembrane """"""""receptor like"""""""" protein which shows striking homology to mammalian epidermal growth factor. The available molecular, embryological and genetic evidence suggest the existence of a cell interaction mechanism which is essential for the correct differentiation of the early ectoderm into neural and epidermal precursors. The Notch locus is essential for wild type development not only during embryogenesis but also during later developmental stages. Genetic analysis has revealed the existence of mutations affecting postembryonic developmental stages and the molecular analysis has associated specific lesions to several such mutations. Coincident with the separation of the developing nervous system from the epidermis a substantial number of developing epidermal cells die as part of the normal developmental program. The role cell interactions, and by extension the neurogenic genes, play in this developmentally programmed cell death is not yet clear. Moreover the physiological manifestation of Notch malfunction, as revealed by genetic analysis in the adult, raise the possibility that wild type Notch activity may be important for the maintenance of the differentiated state of neural structures, such as ommatidia. In order to address these issues at the molecular level we propose to extend the analysis of the Notch locus by examining its biochemical involvement in cell communication. We will use the available molecular probes to isolate and characterize the Notch protein as well as to examine its subcellular localization. We propose to use whole animal transformation in conjuction with in vitro mutagenesis in order to examine experimentally functional aspects of the Notch protein and its involvement in cell interactions.
| 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 |
| 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 |
| Dimitriadi, Maria; Sleigh, James N; Walker, Amy et al. (2010) Conserved genes act as modifiers of invertebrate SMN loss of function defects. PLoS Genet 6:e1001172 |
| 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 |
| 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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