Blumenthal, E. M. | Search bioRxiv

bioRxiv2024

Loss of glia-neuronal interactions and age-dependent cell death in a Drosophila model of adult neurodegeneration

While glial dysfunction has been implicated in the development of multiple neurodegenerative diseases, the role of glial cell morphology in neurodegeneration is underexplored. In the fruit fly Drosophila melanogaster, mutants of the gene drop-dead (drd) exhibit adult neurodegeneration and extremely short lifespans. The morphology of one class of glia, the cortex glia (CG), is abnormal in drd mutants. In controls, the CGs form a continuous network that wraps around all neuronal cell bodies, but in drd mutants, individual CGs are stunted and the CG network is disrupted. These phenotypes are present on the first day of adulthood. Apoptosis is the central mechanism of cell death in drd mutants; widespread cell death is observed on the first day of adulthood and increases with age and is primarily neuronal. Apoptotic cells are found both within and outside of the remaining CG network, with significant variation in the distribution among individual brains. The degree of cell death and CG network breakdown in young adults could explain why drd mutant flies die within the first week of adulthood. The Drosophila drd mutant is a unique model of adult neurodegeneration that provides new insight into the breakdown in interaction between glia and neuronal cell bodies.

neuroscience↗

bioRxiv2023

The Drosophila drop-dead gene is required for eggshell integrity

The eggshell of the fruit fly Drosophila melanogaster is a useful model for understanding the synthesis of a complex extracellular matrix. The eggshell is synthesized during mid-to-late oogenesis by the somatic follicle cells that surround the developing oocyte. We previously reported that female flies mutant for the gene drop-dead (drd) are sterile, but the underlying cause of the sterility remained unknown. In this study, we examined the role of drd in eggshell synthesis. We show that eggs laid by drd mutant females are fertilized but arrest early in embryogenesis, and that the innermost layer of the eggshell, the vitelline membrane, is abnormally permeable to dye in these eggs. In addition, the major vitelline membrane proteins fail to become crosslinked by nonreducible bonds, a process that normally occurs during egg activation following ovulation, as evidenced by their solubility and detection by Western blot in laid eggs. In contrast, the Cp36 protein, which is found in the outer chorion layers of the eggshell, becomes crosslinked normally. To link the drd expression pattern with these phenotypes, we show that drd is expressed in the ovarian follicle cells beginning in mid-oogenesis, and, importantly, that all drd mutant eggshell phenotypes could be recapitulated by selective knockdown of drd expression in the follicle cells. To determine whether drd expression was required for the crosslinking itself, we performed in vitro activation and crosslinking experiments. The vitelline membranes of control egg chambers could become crosslinked either by incubation in hyperosmotic medium, which activates the egg chambers, or by exogenous peroxidase and hydrogen peroxide. In contrast, neither treatment resulted in the crosslinking of the vitelline membrane in drd mutant egg chambers. These results indicate that drd expression in the follicle cells is necessary for vitelline membrane proteins to serve as substrates for peroxidase-mediated cross-linking at the end of oogenesis.

developmental biology↗