live-imaging-apoptotic-cell-clearance-during-drosophila

Live Imaging of Apoptotic Cell Clearance during <em>Drosophila </em>Embryogenesis

The  proper elimination of unwanted or aberrant cells through apoptosis and  subsequent phagocytosis (apoptotic cell clearance) is crucial for normal  ...

Technion-Israel Institute of Technology

The removal of apoptotic cells by phagocytic neighbors is essential for metazoan development but remains poorly characterized. Here we report the discovery of a Drosophila phagocytosis receptor, Six-microns-under (SIMU), which is expressed in highly phagocytic cell types during development and required for efficient apoptotic cell clearance by glia in the nervous system and by macrophages elsewhere. SIMU is part of a conserved family of proteins that includes CED-1 and Draper (DRPR). Phenotypic analysis reveals that simu acts upstream of drpr in the same pathway and affects the recognition and engulfment of apoptotic cells, while drpr affects their subsequent degradation. SIMU strongly binds to apoptotic cells, presumably through its EMILIN-like domain, but requires no membrane anchoring, suggesting that it can function as a bridging molecule. Our study introduces an important factor in tissue-resident apoptotic clearance and underscores the prominent role of glia as "semiprofessional" phagocytes in the nervous system.

Six-microns-under acts upstream of Draper in the glial phagocytosis of apoptotic neurons.

Elimination of unwanted and potentially harmful matter is crucial for nervous system development and function. Glia are the main cleaners of the CNS that perform their function through engulfment and degradation of dying neurons and degenerating neuronal branches, developing excessive axons and synapses. Recent studies in Drosophila melanogaster have enhanced significantly our understanding of the phagocytic functions of glia and demonstrated that Drosophila provides an excellent model for investigating the molecular and cellular basis of glial phagocytosis. The current knowledge and great potential of this model, which is reviewed here, can open new directions in mammalian glial biology.

Keeping the CNS clear: glial phagocytic functions in Drosophila.

Clearance of apoptotic cells by phagocytic neighbors is crucial for normal development of multicellular organisms. However, how phagocytes discriminate between healthy and dying cells remains poorly understood. We focus on glial phagocytosis of apoptotic neurons during development of the Drosophila central nervous system. We identified phosphatidylserine (PS) as a ligand on apoptotic cells for the phagocytic receptor Six Microns Under (SIMU) and report that PS alone is not sufficient for engulfment. Our data reveal that, additionally to PS exposure, caspase activity is required for clearance of apoptotic cells by phagocytes. Here we demonstrate that SIMU recognizes and binds PS on apoptotic cells through its N-terminal EMILIN (EMI), Nimrod 1 (NIM1), and NIM2 repeats, whereas the C-terminal NIM3 and NIM4 repeats control SIMU affinity to PS. Based on the structure-function analysis of SIMU, we discovered a novel mechanism of internal inhibition responsible for differential affinities of SIMU to its ligand which might prevent elimination of living cells exposing PS on their surfaces.

Estee Kurant

Department of Anatomy and Cell Biology and the Rappaport Institute for Research in the Medical Sciences,
Rappaport Faculty of Medicine,
Department of Anatomy and Cell Biology and the Rappaport Institute for Research in the Medical Sciences, Rappaport Faculty of Medicine

Technion-Israel Institute of Technology

Live Imaging of Apoptotic Cell Clearance during Drosophila Embryogenesis