Regulation of drosophila development by MAP kinase pathways

Abstract

During developmental processes, cells undergo dramatic physiological changes by regulating various signal transduction pathways, which result in the determination of cell fates among proliferation, differentiation and cell death. Among various signaling pathways involved in these processes, MAP kinase (MAPK) pathways play critical roles particularly at the initiation step of cell fate determination. A family of MAPK pathways is composed of 4 subgroups, the ERK-MAPK, the JNK-MAPK, the p38-MAPK and the ERK5 signaling cascades. In Drosophila, the ERK-MAPK pathway regulates normal development of eye and wing, and the JNK-MAPK pathway is involved in the regulation of apoptosis and other developmental processes including dorsal and thorax closure processes. To further elucidate details behind the MAPK pathway-dependent Drosophila development, first, I have characterized Drosophila DLK as a novel component of the JNK-MAPK pathway. Drosophila DLK genetically interacted with the components of the JNK-MAPK pathway and strongly induced JNK-MAPK activation in eyes, which resulted in a highly increased apoptotic cell death. Next, I conducted genetic analyses for functional interactions between MAPK pathways and various signaling molecules including tensin and PTEN as representative signaling components for integrin- and PI3K-dependent signaling pathways, respectively. The JNK-MAPK pathway genetically interacted with tensin for proper attachment of dorsal and ventral wing surfaces during wing development. PTEN indirectly activated the ERK-MAPK pathway by inhibiting Akt activity, which blocks Raf activation during eye and wing development. Finally, using Drosophila as a model system, I have showed that properly myristylated HIV-1 protein Nef induced a caspase-dependent apoptosis by activating the JNK-MAPK pathway in a cell-autonomous manner. Collectively, these results support that two distinct MAPK pathways, the ERK-MAPK and the JNK-MAPK signaling cascades, are highly involv...