The goal of the proposed research is to achieve a better understanding of the mechanisms by which Delta, a ligand for the Notch receptor, affects cell fate specification during development in the fruit fly, Drosophila melanogaster. Delta-Notch-mediated signalling inhibits the adoption of a particular cell fate, induced in response to a particular inductive cue, by the majority of cells within an equipotent group o cells (i.e., equivalence group). Developmental fates are thereby partitioned among cells within equivalence groups: uninhibited cells respond to """"""""early"""""""" inductive cues, and inhibited cell maintain pleuripotence and adopt alternative fates in response to """"""""later"""""""" inductive cues. Elucidation of aspects of the mechanism by which Delta-Notch signalling regulates Delta and Notch expression in vivo will involve analysis of Delta and Notch expression in somatic clones with reduced or elevated signalling activity, and immunohistochemical analysis of the abilities of known neurogenic pathway elements to affect Notch-dependent Delta down-regulation. Investigation of mechanisms of Delta signal activation and inactivation will involve molecular genetic analysis of genes that encode functions that activated Delta signalling, cell biological analysis of intercellular transfer of Delta, and structural and functional analyses of trafficking-defective Delta variants. Analysis of structural requirements for Delta signalling in vivo will involve functional analyses in germ line transformants of Delta variants that cannot bind to Notch and/or Delta, a secreted version of the Delta extracellular domain, and Delta variants with EGF motif-specific mutations, and structural and functional analysis of molecular lesions that inactivate Delta function, but do not eliminated the Delta protein. The discovery of Delta and Notch homologs in a variety of metazoans, including humans, and the correlation of aberrant Notch genes with a subset of T cell lymphomas implies that this research will prove relevant to understanding the roles of Delta- mediated signalling in development and disease in many metazoans, including ourselves. The fact that Delta-mediating signalling can preserve the pleuripotence of cell populations suggest that Delta- Notch signalling may be employed to generate cell populations for cell replacement therapies designed to combat injury and degenerative diseases in humans.
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