The proposed research is concerned with the mechanisms underlying differential gene expression and pattern formation in eucaryotic development. Our study aims at the molecular characterization of genetic loci which affect the ectodermal differentiation in the very early embryo of Drosophila melanogaster. Genetic analysis has revealed that the early differentiation of the ectoderm into epidermal precursor cells and neuroblasts is under the genetic control of a small group of genes. The best characterized locus among this group is the Notch locus. Notch mutations fundamentally affect the differentiation of the ectoderm in the embryo by interfering in an unknown fashion with the normal developmental program, causing the hypertrophy of the nervous system. We initiated a molecular study of this developmentally significant locus in an attempt to gain insight into its biochemical nature and its mode of action during development. During the last two years we were able to isolate the DNA sequences which define the Notch locus, construct a physical map and correlated it to the genetic map, construct and analyse several new Notch alleles and define the transcriptional activity of the cloned sequences. This work has indicated the necessity for a more detailed analysis. We propose the continuation of the molecular characterization of the Notch locus by exploring in greater depth its structural features, its expression and mode of action during development and by isolating and characterizing the gene product.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM029093-06
Application #
3276589
Study Section
Genetics Study Section (GEN)
Project Start
1981-04-01
Project End
1989-03-31
Budget Start
1986-04-01
Budget End
1987-03-31
Support Year
6
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Yale University
Department
Type
Schools of Arts and Sciences
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Busseau, I; Diederich, R J; Xu, T et al. (1994) A member of the Notch group of interacting loci, deltex encodes a cytoplasmic basic protein. Genetics 136:585-96
Fehon, R G; Dawson, I A; Artavanis-Tsakonas, S (1994) A Drosophila homologue of membrane-skeleton protein 4.1 is associated with septate junctions and is encoded by the coracle gene. Development 120:545-57
Dawson, I A; Roth, S; Akam, M et al. (1993) Mutations of the fizzy locus cause metaphase arrest in Drosophila melanogaster embryos. Development 117:359-76
Rebay, I; Fehon, R G; Artavanis-Tsakonas, S (1993) Specific truncations of Drosophila Notch define dominant activated and dominant negative forms of the receptor. Cell 74:319-29
Delidakis, C; Artavanis-Tsakonas, S (1992) The Enhancer of split [E(spl)] locus of Drosophila encodes seven independent helix-loop-helix proteins. Proc Natl Acad Sci U S A 89:8731-5
Xu, T; Caron, L A; Fehon, R G et al. (1992) The involvement of the Notch locus in Drosophila oogenesis. Development 115:913-22
Delidakis, C; Preiss, A; Hartley, D A et al. (1991) Two genetically and molecularly distinct functions involved in early neurogenesis reside within the Enhancer of split locus of Drosophila melanogaster. Genetics 129:803-23
Artavanis-Tsakonas, S; Delidakis, C; Fehon, R G (1991) The Notch locus and the cell biology of neuroblast segregation. Annu Rev Cell Biol 7:427-52
Fehon, R G; Johansen, K; Rebay, I et al. (1991) Complex cellular and subcellular regulation of notch expression during embryonic and imaginal development of Drosophila: implications for notch function. J Cell Biol 113:657-69
Markopoulou, K; Artavanis-Tsakonas, S (1991) Developmental analysis of the facets, a group of intronic mutations at the Notch locus of Drosophila melanogaster that affect postembryonic development. J Exp Zool 257:314-29

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