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In vivo analysis of neuronal clearance by microglia uncovers a new compartment in the phagocytic pathway

Villani, Ambra

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Abstract

Clearance of apoptotic cells by professional, tissue resident macrophages is crucial during development, maintenance of tissue homeostasis and disease. Phagocytic cells can engulf and process several dying cells with high efficiency while still maintaining their dynamic behaviour and morphology. Effective intracellular processing of ingested cells is likely to be crucial for the phagocyte to function, but the underlying cellular mechanisms are poorly understood. Here, we investigate this by focusing on microglia, the tissue resident macrophages of the Central Nervous System (CNS). In particular, we take advantage of the optical transparency of the zebrafish embryo and apply a combination of genetic, chemical and imaging approaches to study phagocytosis of neurons in vivo. In this study we focus on bubblebrain (blb), a zebrafish mutant that has bloated microglia. The cell body of blb microglia is occupied by a single large vesicle that grows progressively. By comparing wild type and blb embryos we discovered that efficient processing of engulfed neurons depends on the shrinkage and packaging of phagosomes into the gastrosome, a unique cellular compartment with distinct ultra-structural and molecular features. Moreover, we show that the blb phenotype is caused by lack of Slc37a2, a putative glucose-6-phosphate transporter localized on phagosomes. Loss of Slc37a2 prevents phagosomal shrinkage, and this in turn results in the expansion of the gastrosome and in the dramatic bloating of the cell. Interestingly, we show that gastrosomal defects impact on microglial activities and affect the ability of these cells to engulf neurons and to migrate towards brain injuries. Thus, this work provides experimental evidence for the existence of the gastrosome, a critical new component of the phagocytic pathway that allows easy manipulation of key microglial activities in vivo.

Item Type: Dissertation
Supervisor: Mueller, Prof. Dr. Ulrike
Date of thesis defense: 14 December 2018
Date Deposited: 06 Mar 2019 07:03
Date: 2019
Faculties / Institutes: The Faculty of Bio Sciences > Institute of Pharmacy and Molecular Biotechnology
Subjects: 000 Generalities, Science
500 Natural sciences and mathematics
570 Life sciences
Controlled Keywords: phagocytosis, microglia, macrophages, apoptotic cell clearance, zebrafish
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