The scoop on the fly brain: glial engulfment functions in Drosophila

Abstract

Glial cells provide support and protection for neurons in the embryonic and adult brain, mediated in part through the phagocytic activity of glia. Glial cells engulf apoptotic cells and pruned neurites from the developing nervous system, and also clear degenerating neuronal debris from the adult brain after neural trauma. Studies indicate that Drosophila melanogaster is an ideal model system to elucidate the mechanisms of engulfment by glia. The recent studies reviewed here show that many features of glial engulfment are conserved across species and argue that work in Drosophila will provide valuable cellular and molecular insight into glial engulfment activity in mammals.

Keywords: Drosophila glia; Phagocyte; phagocytosis.

Fig. 1. Recognition and engulfment of target cells

(a) Some engulfment targets secrete chemoattractants to entice migratory phagocytes to ‘come-get-me’. (b) Phagocytes recognize targets for engulfment through activation of phagocytic immune receptors that bind ‘eat-me’ tags presented on the surface of engulfment targets. (c) These immune receptors then activate downstream signaling cascades that allow phagocytes to extend pseudopodial projections and, ultimately, envelop and completely internalize the target cell into a phagosome compartment. (d) Engulfed material is then digested efficiently within the confines of the phagolysosome.

Fig. 2. Schematic models of glial engulfment in the Drosophila nervous system

(A) Glial cells engulf apoptotic neuron corpses in the embryo: Cartoon of a cross-section through a late stage (stage 15/16) embryonic CNS showing only surface glial subtypes (green). Most apoptotic corpses (tan) occur in surface glia (green), particularly within ventral regions of the CNS. After corpses are engulfed, they may be destroyed by glia through lysosomal destruction or possibly transferred to macrophages (pink) that reside outside of the CNS (indicated by question mark). See text for more details. (B) Glia engulf pruned neurites during metamorphosis: At late larval stages, mushroom body (MB) gamma neurons project a single axon extension that bifurcates into the dorsal and medial lobes of the MB. By 6 hours after puparium formation (APF), gamma neuron axons begin to display signs of ‘blebbing’ (arrowheads), and glial cell bodies (green) have accumulated around the dorsal and medial lobes of the MB. Over the next 12 hours, glial membranes invade the MB lobes and engulf fragments of degenerating gamma neuron axons as they are pruned. Glia also engulf degenerating gamma neuron dendrites during this time. (C) Mature glia engulf degenerating olfactory receptor neuron (ORN) axons after injury: ORN cell bodies reside in either the third antennal segments (purple) or maxillary palps (orange) and send axonal projections into the brain where they synapse on antennal lobe (AL) glomeruli. Antennal or maxillary palp ORN axons can be selectively severed by surgical ablation of these olfactory organs. Within hours after injury, severed ORN axons fragment into smaller pieces, and glial cell membranes accumulate specifically on AL glomeruli that contain severed axons to begin engulfing fragmented axon debris.

Fig. 3. Current model of corpse recognition and engulfment in C. elegans

Studies in C. elegans have identified two, parallel, partially redundant pathways that are involved in the recognition and engulfment of apoptotic cells. One pathway drives engulfment activity through the receptor CED-1, the adaptor protein CED-6 and the ABC-transporter CED-7, whereas a second pathway signals via the CED-2, CED-5 and CED-12 complex. The phosphatidylserine receptor (PS-R) is placed genetically upstream of the CED-2/5/12 complex (indicated with dotted arrow), but there are probably other recognition receptors that also function within this pathway (indicated by ?). Each engulfment pathway drives phagocytosis through active remodeling of the actin cytoskeleton. See text for more details.

Fig. 4. Multiple isoforms of Draper are present in Drosophila

C. elegans CED-1 and all Drosophila Draper isoforms are single-pass transmembrane proteins. The extracellular domain (ECD) of CED-1 contains 16 EGF-like repeats (ovals) and might bind ‘eat-me’ signals presented by cell corpses. Two tyrosine phosphorylation sites within the intracellular domain of CED-1 (NPXY and YXXL) are required for engulfment activity in worm phagocytes. CED-6 interacts with the NPXY motif (Su et al., 2002), but it is unknown how the YXXL domain is involved in transducing CED-1 signaling (indicated by ?). The longest isoform of Draper (Draper I) is most similar to CED-1 and has 15 EGF-like repeats (ovals) in the extracellular domain, whereas the shorter isoforms contain five EGF-like motifs.