Draper‐mediated JNK signaling is required for glial phagocytosis of apoptotic neurons during <i>Drosophila</i> metamorphosis

Hilu‐Dadia, Reut; Hakim-Mishnaevski, Ketty; Levy-Adam, Flonia; Kurant, Estee

doi:10.1002/glia.23322

Cited by 35 publications

(31 citation statements)

References 48 publications

(73 reference statements)

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“…Confirming antibody specificity, cortex glial RNAi-mediated knockdown of all Drpr isoforms results in a 49% decrease in Drpr levels (Figure 3F), and cortex glial RNAi-mediated knockdown of Drpr-I, the isoform that promotes debris clearance, results in a 53% decrease (Figures 3B and 3F;Logan et al, 2012). As expected, drpr nulls exhibit a vast excess of apoptotic debris (Figures 3L and 3M) (Hilu-Dadia et al, 2018). And in line with a previous report (Etchegaray et al, 2016), we find that Drpr functions specifically in cortex glia since cortex-glial-specific knockdown of all Drpr isoforms ( Figures 3K-3N Figures 3E and 3G).…”

Section: Toll-6-foxo Signaling Regulates Draper Transcription In Cortsupporting

confidence: 73%

“…Third, Drpr overexpression fully rescues increased Dcp-1 accumulation in pathway mutants. Since Drpr is the primary engulfment receptor in the CNS (Hilu-Dadia et al, 2018;Tasdemir-Yilmaz and Freeman, 2014), these results demonstrate that phagocytosis is specifically impaired in the mutants. Fourth, pathway over-activation results in reduced apoptotic debris, consistent with the hypothesis that this ''priming'' pathway normally accelerates debris clearance.…”

Section: Discussionmentioning

confidence: 66%

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Dying Neurons Utilize Innate Immune Signaling to Prime Glia for Phagocytosis during Development

et al. 2019

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Graphical Abstract Highlights d Dying neurons signal to phagocytic glia via a Toll receptor pathway during development d Dying neurons activate Furin-dependent processing of the Toll-6 ligand, Spz5 d Cortex glia sense cleaved Spz5 via Toll-6-dSARM signaling d Toll-6 signaling drives transcriptional upregulation of the Draper engulfment receptor SUMMARYGlia continuously survey neuronal health during development, providing trophic support to healthy neurons while rapidly engulfing dying ones. These diametrically opposed functions necessitate a foolproof mechanism enabling glia to unambiguously identify those neurons to support versus those to engulf. To ensure specificity, glia are proposed to interact with dying neurons via a series of carefully choreographed steps. However, these crucial interactions are largely obscure. Here we show that dying neurons and glia communicate via Toll-receptor-regulated innate immune signaling. Neuronal apoptosis drives processing and activation of the Toll-6 ligand, Sp € atzle5. This cue activates a dSARM-mediated Toll-6 transcriptional pathway in glia, which controls the expression of the Draper engulfment receptor. Pathway loss drives earlyonset neurodegeneration, underscoring its functional importance. Our results identify an upstream priming signal that prepares glia for phagocytosis. Thus, a core innate immune pathway plays an unprecedented role setting the valence of neuron-glia interactions during development.Developmental Cell 48, 506-522, February 25, 2019 507 on the manuscript. We also appreciate helpful discussions with members of the Broihier and Landreth labs.

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Section: Toll-6-foxo Signaling Regulates Draper Transcription In Cortsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 66%

Dying Neurons Utilize Innate Immune Signaling to Prime Glia for Phagocytosis during Development

et al. 2019

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“…While previous studies have demonstrated that JNK signaling is upregulated in glia in response to neuronal injury and plays a role in promoting glial phagocytosis of neurons during development, the role of JNK signaling in gliogenesis has been largely unexplored [ 48 – 50 ]. Studies in the embryo showed that mutation of zinc finger homeodomain 1 ( zfh1 ) promoted apoptosis of ePG10 in a JNK-dependent manner, although Zfh1 was expressed in all ePGs [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of raw as a regulator of glial development

2018

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Glial cells perform numerous functions to support neuron development and function, including axon wrapping, formation of the blood brain barrier, and enhancement of synaptic transmission. We have identified a novel gene, raw, which functions in glia of the central and peripheral nervous systems in Drosophila. Reducing Raw levels in glia results in morphological defects in the brain and ventral nerve cord, as well as defects in neuron function, as revealed by decreased locomotion in crawling assays. Examination of the number of glia along peripheral nerves reveals a reduction in glial number upon raw knockdown. The reduced number of glia along peripheral nerves occurs as a result of decreased glial proliferation. As Raw has been shown to negatively regulate Jun N-terminal kinase (JNK) signaling in other developmental contexts, we examined the expression of a JNK reporter and the downstream JNK target, matrix metalloproteinase 1 (mmp1), and found that raw knockdown results in increased reporter activity and Mmp1 levels. These results are consistent with previous studies showing increased Mmp levels lead to nerve cord defects similar to those observed upon raw knockdown. In addition, knockdown of puckered, a negative feedback regulator of JNK signaling, also causes a decrease in glial number. Thus, our studies have resulted in the identification of a new regulator of gliogenesis, and demonstrate that increased JNK signaling negatively impacts glial development.

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“…Moreover, a specific cell type likely differs only in the expression of the limited number of genes which confer a new function to it [10,11]. In this study, we used a publicly available expression profile of 55,000 single cells of Drosophila optic lobe in order to find novel molecular markers for specific cell types, following by experimental confirmation of the predicted results.…”

Section: Introductionmentioning

confidence: 96%

Astrocyte-like glia-specific gene deathstar is crucial for normal development, adult locomotion and lifespan of male Drosophila

Najafi

Wong

Kim

2019

Preprint

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Background: Drosophila melanogaster is a proper model organism for studying the development and function of the nervous system. The Drosophila nervous system consists of distinct cell types with significant homologies to various cell types of more advanced organisms, including human. Among all cell types of the nervous system, astrocyte-like glia (ALG) have conserved functions to mammals and are essential for normal physiology and behaviours of the fly.Results: In this study, we exploited the gene expression profile of single cells in Drosophila optic lobe to identify the genes with specific expression pattern in each cell type. Through a bioinformatical analysis of the data, a novel ALG-specific gene (here assigned as deathstar) was identified. Immunostaining of deathstar in the central nervous system (CNS) showed its presence in specific regions of Drosophila ventral nerve cord, which previously has been characterized as ALG cells. Consistent with the bioinformatical analysis, deathstar-related signals were overlapped with the signals of the previously-reported ALG marker, Eaat1, supporting its specific expression in ALG cells. At the physiological level, RNAi-mediated suppression of deathstar gene impeded the normal development of male flies without any effects on females. Cell type-specific expression of deathstar RNAi showed that deathstar gene affects locomotion behaviour and lifespan of D. melanogaster, in an ALG-specific manner.Conclusions: Taken together, we showed that bioinformatical analysis of a previously reported expression data of Drosophila optic lobe successfully predicted the ALG-specific expression pattern of deathstar gene. Moreover, it was consistent with the ALG-specific effects of this gene on locomotion and lifespan of D. melanogaster, in vivo.

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Draper‐mediated JNK signaling is required for glial phagocytosis of apoptotic neurons during Drosophila metamorphosis

Cited by 35 publications

References 48 publications

Dying Neurons Utilize Innate Immune Signaling to Prime Glia for Phagocytosis during Development

Dying Neurons Utilize Innate Immune Signaling to Prime Glia for Phagocytosis during Development

Identification of raw as a regulator of glial development

Astrocyte-like glia-specific gene deathstar is crucial for normal development, adult locomotion and lifespan of male Drosophila

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