Abstract
BackgroundThe subcellular localization of membrane and secreted proteins is finely and dynamically regulated through intracellular vesicular trafficking for permitting various biological processes. Drosophila Amyloid precursor protein like (APPL) and Hikaru genki (HIG) are examples of proteins that show differential subcellular localization among several developmental stages.Methodology/Principal FindingsDuring the study of the localization mechanisms of APPL and HIG, we isolated a novel mutant of the gene, CG1973, which we named yata. This molecule interacted genetically with Appl and is structurally similar to mouse NTKL/SCYL1, whose mutation was reported to cause neurodegeneration. yata null mutants showed phenotypes that included developmental abnormalities, progressive eye vacuolization, brain volume reduction, and lifespan shortening. Exogenous expression of Appl or hig in neurons partially rescued the mutant phenotypes of yata. Conversely, the phenotypes were exacerbated in double null mutants for yata and Appl. We also examined the subcellular localization of endogenous APPL and exogenously pulse-induced APPL tagged with FLAG by immunostaining the pupal brain and larval motor neurons in yata mutants. Our data revealed that yata mutants showed impaired subcellular localization of APPL. Finally, yata mutant pupal brains occasionally showed aberrant accumulation of Sec23p, a component of the COPII coat of secretory vesicles traveling from the endoplasmic reticulum (ER) to the Golgi.Conclusion/SignificanceWe identified a novel gene, yata, which is essential for the normal development and survival of tissues. Loss of yata resulted in the progressive deterioration of the nervous system and premature lethality. Our genetic data showed a functional relationship between yata and Appl. As a candidate mechanism of the abnormalities, we found that yata regulates the subcellular localization of APPL and possibly other proteins.
Highlights
Transmembrane and secreted proteins are synthesized in the endoplasmic reticulum (ER) and are transported to their final destinations, such as the cell surface, by means of vesicular trafficking
Our genetic data showed a functional relationship between yata and Appl
Identification of yata as a genetically-interacting molecule of Appl While studying the localization mechanisms of Amyloid precursor protein like (APPL) and Hikaru genki (HIG), we made a transgenic fly with an insertion of a P-element containing the HIG minigene in the third chromosome
Summary
Transmembrane and secreted proteins are synthesized in the ER and are transported to their final destinations, such as the cell surface, by means of vesicular trafficking This process is tightly regulated both spatially and temporally to establish the proper subcellular distribution of molecules for permitting various biological processes. APPL is suggested to be involved in the formation of larval neuromuscular synapses by regulation of the cell adhesion molecule, Fasciclin II [1,5,6] It regulates axonal transport, and gene dosages of motor proteins affect the phenotype caused by overexpression of APPL [7,8]. Drosophila Amyloid precursor protein like (APPL) and Hikaru genki (HIG) are examples of proteins that show differential subcellular localization among several developmental stages
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