| Many significant developmental and pathogenic processes require the Jun N-terminal kinase (JNK) signaling cascade. Using the powerful genetic model organism, Drosophila melanogaster, and specifically the morphogenetic event of embryonic dorsal closure, many components and regulators of the Drosophila JNK (DJNK) cascade have been identified and examined. Dorsal closure is a cell shape change driven event in which the lateral epidermis moves dorsally until the entire embryo is encased in epidermis. Genes required for dorsal closure are often identified by their characteristic mutant cuticular phenotype, a hole in the dorsal surface of the cuticle. For proper dorsal closure to occur, DJNK signaling is required in the dorsal-most epidermal cells, the leading edge (LE) cells.;Study of the negative regulation of DJNK provides insight into the mechanism and management of this critical signaling cascade. Presented in this dissertation is the characterization of a novel antagonist of DJNK, raw. We find the function of Raw is to limit DJNK signaling to only the LE cells, and that Raw is required broadly in the epidermis to antagonize DJNK. These data establishes a new perspective for DJNK during dorsal closure, refining previous models of the activity of DJNK by suggesting the epidermis is broadly competent for DJNK and providing insight into the spatial restrictions of the DJNK initiating signal(s). Mechanistic studies of the raw group antagonists (raw, rib and puc) offer evidence that the raw group provides multiple tiers of DJNK regulation. Raw and Puc act independently and Raw and Rib may act together to antagonize DJNK signaling. Finally, Raw and Rib are the first described antagonists of DJNK that are not phosphatases.;Continued investigation into the mechanism of Drosophila antagonists will open new areas of research into DJNK regulation. Further study of these novel DJNK antagonists will contribute to our knowledge of the regulation and mechanism of this key signaling pathway. These studies can be further utilized to establish models in which to study human disease processes that require JNK. |
