Successful developmental processes require two things: 1) proper timing, and 2) proper positioning. These two factors are, by and large, linked. For example, a decrease in responsiveness to a growth factor may extinguish a mitogenic or chemoattractive effect, while an increase in responsiveness to an environmental cue may have the opposite effect. Cell death can be considered a timing event, one that is widely used during embryogenesis. There are two types of cell death: necrosis and apoptosis. For cell death to be effective during development, it must come in the right form. Necrosis is initiated by external events, characterized by cell rupture, and results in inflammation. In contrast, apoptosis is initiated internally, mediated by caspases, and does not trigger inflammation.1 Necrotic cell death is often accompanied by scarring, an outcome that may be acceptable in wounded tissue, but is never acceptable in newly created tissue. Apoptosis, if properly regulated, eliminates unwanted cells without damaging the structural integrity of the surrounding tissue. Thus, this form of cell death is highly preferred during development.
||Jedi-1 and MEGF10 on Satellite Glial Cell Precursors Mediate the Phagocytosis of Apoptotic Neurons During Embryonic Development. During embryonic development, neural crest cells migrate ventrolaterally to a position destined to become the dorsal root ganglia (DRG). Some cells become neuroblasts (light green), while others form support cells such as satellite glial cell precursors (blue). Depending upon the neuronal phenotype, specific neurotrophic factors are required for cell survival. Inadequate exposure to a required growth factor initiates an apoptotic program. Apoptotic neuroblasts are cleared via phagocytosis by satellite glial cell precursors. This process involves the transmembrane molecules Jedi-1 and MEGF10.
Apoptosis during embryogenesis has recently been studied in the mammalian dorsal root ganglia (DRG). During embryonic development, neural crest cells migrate laterally from the superior aspect of the neural trunk. These cells form cellular aggregates that have the potential to generate glia and more than 20 different neuronal cell types.2 Notably, up to 50% of all cells destined to become neurons will ultimately be removed via apoptosis. The cells responsible for debris removal are satellite glial cell (SGC) precursors.3 This is somewhat surprising given that cells typically involved in the removal of cellular debris are phagocytes belonging to the macrophage/microglia lineage. In the mouse embryonic DRG, however, Wu et al. discovered that SGC precursors were properly placed, sufficiently plentiful, and fully capable of removing dead neuronal cells from embryonic day E11 through E15 (equivalent to day 31 through day 77 in human). Wu et al. identified two particular molecules that contribute to the phagocytic process, MEGF10 (multiple EGF domains protein 10), and MEGF12/Jedi-1 (Jagged and Delta-1), a 150 kDa type I transmembrane glycoprotein also known as PEAR-1 in human.4 Although the ligand(s) for Jedi-1 is unknown, data suggest that MEGF10 and Jedi-1 interact to form a functional complex.
The potential importance of Jedi-1 (and MEGF10) in satellite cell precursor activity is twofold. First, it presumably imparts satellite cells with a phagocytic capacity that meets the rate of neuronal cell death. As long as dying cells retain their cell membrane, pro-inflammatory mediators such as HSP70 and HSP96 remain intracellular, and inflammation is suppressed. But if the apoptotic program ends and secondary necrosis begins (due to an inability to increase the rate of phagocytosis), HSPs are released, leading to macrophage-mediated cytokine secretion and dendritic cell activation.5 Second, the use of receptors such as Jedi-1 apparently contributes to a tolerogenic form of antigen processing. Wu et al. found that inflammation was absent in the DRG.3 Other glia, such as astrocytes, are reported to remove necrotic neurons in the absence of microglial stimulation. While the data is mixed, astrocytes are reported to be both tolerogenic and immunogenic, depending upon the experimental design.6, 7 Thus, there is a precedent for glial-mediated induction of tolerance. Coupled with this is the observation that once secondary necrosis begins, an aberrant form of antigen processing ensues, exposing antigenic epitopes that otherwise are not detectable. This is suggested to predispose an animal to later autoimmunity, and emphasizes the importance of timely debris removal.8
On balance, it would appear that Jedi-1 and its related family members likely play a significant role in the creation of an environment that is both developmentally friendly and homeostatically secure.
- Savill, J. et al. (2002) Nat. Rev. Immunol. 2:965.
- Raible, D.W. & J.M. Ungos (2006) Adv. Exp. Med. Biol. 589:170.
- Wu, H-H. et al. (2009) Nat. Neurosci. 12:1534.
- Krivtsov, A.V. et al. (2007) J. Cell. Biochem. 101:767.
- Basu, S. et al. (2000) Int. Immunol. 12:1539.
- Constantinescu, C.S. et al. (2005) J. Neurochem. 95:331.
- Falsig, J. et al. (2006) J. Neurochem. 96:893.
- Hall, J.C. et al. (2004) Rheum. Dis. Clin. N. Am. 30:455.
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