Removing apoptotic cells by phagocytic neighbors is essential for metazoan development

Removing apoptotic cells by phagocytic neighbors is essential for metazoan development Rabbit polyclonal to ACTBL2. but remains poorly characterized. but BRL-49653 requires no membrane anchoring suggesting that it can function as a bridging molecule. Our study introduces an important new factor in tissue-resident apoptotic clearance and underscores the prominent role of glia as ‘semi-professional’ phagocytes in the nervous system. Introduction The elimination of superfluous or damaged cells through programmed cell death plays an essential role in metazoan development and tissue homeostasis; its critical final stage is the clearance of the apoptotic cells through phagocytosis. The proper recognition uptake and degradation of dying cells is accomplished either by ‘professional’ phagocytes such as macrophages and immature dendritic cells or by ‘non-professional’ tissue-resident neighboring cells. While professional phagocytes have been studied extensively relatively little is known about the biological significance and the molecular underpinnings of tissue-resident phagocytosis (Henson and Hume 2006 Apoptotic cell clearance is a complex process involving recognition engulfment and phagosome formation and maturation as distinct steps (Figure 1E) (for review see Grimsley and Ravichandran 2003 Stuart and Ezekowitz 2005 The apoptotic cell displays distress (‘eat me’) signals that are recognized by the phagocyte either directly by phagocytic receptors or indirectly through bridging molecules (opsonins) supplied systemically through the serum or secreted locally by the phagocyte. Two types of phagocytic receptors have been implicated in this recognition process: without a significant intracellular domain such as CD36 (Franc et al. 1999 Savill et al. 1992 or SRA (Platt and Gordon 1998 and with non-catalytic intracellular domains permitting interaction with other proteins such as CED1 and its homolog DRPR (Freeman et al. 2003 Zhou et al. 2001 or LRP (Ogden et al. 2001 The clustering of both types of BRL-49653 receptors is thought to be required for the recruitment of the downstream machinery to the docking sites which leads to cytoskeletal reorganization and engulfment of the apoptotic cell. The phagocytosis process is completed by the formation of a phagosome and its maturation to a phagolysosome effecting the degradation of the apoptotic particle. Figure 1 Apoptosis and glial phagocytosis in late nervous system development. (A) lateral view of a CM1 stained stage 16 embryo showing that at this developmental stage apoptosis is BRL-49653 largely restricted to the CNS (arrows). (B) ventral and (C) transverse view (from … Insight into the molecular mechanisms by which ‘non-professional’ tissue-resident cells effect apoptotic clearance came initially from the worm which does not have professional phagocytes. Genetic screens identified several phagocytosis genes that fall into two partially redundant pathways one consisting of a phagocytic docking receptor (CED-1) its adaptor (CED-6) an ABC transporter (CED-7) and dynamin and the other of an actin-regulating protein complex (CED-2/5/10/12) that presumably acts downstream of an unknown phagocytic receptor (for review see Mangahas and Zhou 2005 Reddien and Horvitz 2004 Yu et al. 2006 Recently the phosphatidylserine receptor BAI1 was found to act upstream of the homologous complex in mouse (Park et al. 2007 In to date just three factors have already been implicated in apoptotic cell clearance: the macrophage-specific Compact disc36 homolog Croquemort (CRQ; Franc et al. 1999 the F Package proteins Pallbearer (Silva et al. 2007 as well as the broadly indicated CED-1 homolog DRPR which is important in glial phagocytosis of apoptotic neurons (Freeman et al. 2003 A recently available research shows that the apoptotic clearance function of CED-1/DRPR can be conserved in vertebrates (Hamon et al. 2006 Therefore a lot of the players BRL-49653 involved with tissue-resident clearance remain unknown specifically the phagocytic receptors and their cognate ligands for the apoptotic cell. Even more generally an improved knowledge of the mobile and molecular underpinnings of apoptotic clearance can be highly desirable. In the ongoing function presented here we demonstrate that glia will be the primary phagocytes in.