A novel Drosophila injury model reveals severed axons are cleared through a Draper/MMP-1 signaling cascade

Purice, Maria D.; Ray, Arpita; Münzel, Eva Jolanda; Pope, Bernard J.; Park, Daniel J.; Speese, Sean D.; Logan, Mary A.

doi:10.7554/elife.23611

Cited by 59 publications

(84 citation statements)

References 102 publications

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“…Some hints to answering this question may come from the beneficial role played by glial IIS in clearing debris in the nervous system. For instance, signalling through the insulin receptor and AKT upregulates expression of Draper in Drosophila glia after neuronal injury [57]; conversely, decreased IIS in Drosophila glia reduces their ability to clear axonal debris after axotomy [58]. When taken together with our results, these studies present a compelling case for wound healing as one beneficial component of the antagonistically pleiotropic effects of IIS in astrocytes.…”

Section: Discussionsupporting

confidence: 61%

Independent glial subtypes delay development and extend healthy lifespan upon reduced insulin-PI3K signalling

Woodling¹,

Rajasingam²,

Minkley³

et al. 2020

BMC Biol

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Background The increasing age of global populations highlights the urgent need to understand the biological underpinnings of ageing. To this end, inhibition of the insulin/insulin-like signalling (IIS) pathway can extend healthy lifespan in diverse animal species, but with trade-offs including delayed development. It is possible that distinct cell types underlie effects on development and ageing; cell-type-specific strategies could therefore potentially avoid negative trade-offs when targeting diseases of ageing, including prevalent neurodegenerative diseases. The highly conserved diversity of neuronal and non-neuronal (glial) cell types in the Drosophila nervous system makes it an attractive system to address this possibility. We have thus investigated whether IIS in distinct glial cell populations differentially modulates development and lifespan in Drosophila. Results We report here that glia-specific IIS inhibition, using several genetic means, delays development while extending healthy lifespan. The effects on lifespan can be recapitulated by adult-onset IIS inhibition, whereas developmental IIS inhibition is dispensable for modulation of lifespan. Notably, the effects we observe on both lifespan and development act through the PI3K branch of the IIS pathway and are dependent on the transcription factor FOXO. Finally, IIS inhibition in several glial subtypes can delay development without extending lifespan, whereas the same manipulations in astrocyte-like glia alone are sufficient to extend lifespan without altering developmental timing. Conclusions These findings reveal a role for distinct glial subpopulations in the organism-wide modulation of development and lifespan, with IIS in astrocyte-like glia contributing to lifespan modulation but not to developmental timing. Our results enable a more complete picture of the cell-type-specific effects of the IIS network, a pathway whose evolutionary conservation in humans make it tractable for therapeutic interventions. Our findings therefore underscore the necessity for cell-type-specific strategies to optimise interventions for the diseases of ageing.

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Section: Discussionsupporting

confidence: 61%

Independent glial subtypes delay development and extend healthy lifespan upon reduced insulin-PI3K signalling

Woodling¹,

Rajasingam²,

Minkley³

et al. 2020

BMC Biol

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“…In Drosophila, it is involved in developmental neuronal apoptosis during embryogenesis, but is not the main player in this process (Lee et al, 2006;Shklover et al, 2015). With respect to glial phagocytosis, the dJNK pathway has been previously shown to act downstream of Drpr only in pathological conditions such as following axonal injury in the adult brain (Lu et al, 2017;Macdonald et al, 2013) or adult ventral nerve cord (Purice et al, 2017) or concurrently with excessive neuronal death in the embryonic CNS (Shklover et al, 2015). In the normal embryonic or adult CNS, dJNK signaling is not required for glial phagocytosis (Macdonald et al, 2013;Shklover et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…SIMU is required for recognition and engulfment of embryonic apoptotic neurons whereas Drpr is mostly involved in their degradation inside phagosomes (Kurant et al, ). During postembryonic development and in adult flies Drpr is required for elimination of different types of unwanted material that is normally cleared in the CNS and the peripheral nervous system (PNS; Fuentes‐Medel et al, ; Hakim, Yaniv, & Schuldiner, ; Logan et al, ; MacDonald et al, ; Macdonald, Doherty, Hackett, & Freeman, ; Purice et al, ; Ray, Speese, & Logan, ; Tasdemir‐Yilmaz & Freeman ; Ziegenfuss et al, ). In contrast, the function of SIMU during postembryonic development remains unclear.…”

Section: Introductionmentioning

confidence: 99%

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

Hilu‐Dadia

Hakim-Mishnaevski

Levy-Adam

et al. 2018

Glia

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Development of the central nervous system involves elimination of superfluous neurons through apoptosis and subsequent phagocytosis. In Drosophila, this occurs mainly during three developmental stages: embryogenesis, metamorphosis and emerging adult. Two transmembrane glial phagocytic receptors, SIMU (homolog of the mammalian Stabilin-2) and Draper (homolog of the mammalian MEGF10 and Jedi), mediate glial phagocytosis of apoptotic neurons during embryogenesis. However, less is known about the removal of apoptotic neurons during later stages of development. Here we show that during metamorphosis, Draper plays a critical role in apoptotic cell clearance by glia, whereas SIMU, which is mostly expressed in pupal macrophages outside the brain, is not involved in glial phagocytosis. We found that Draper activates Drosophila c-Jun N-terminal kinase (dJNK) signaling predominantly in the ensheathing glia and astrocytes, where it is required for efficient removal of apoptotic neurons. Our data suggest that besides the dJNK pathway, Draper also triggers an additional signaling pathway capable of removing apoptotic neurons in the pupal brain. This study thus reveals that SIMU unexpectedly is not involved in glial phagocytosis of apoptotic neurons during metamorphosis and highlights the novel role of dJNK signaling in developmental apoptotic cell clearance downstream of Draper.

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“…Last, these injury-specific cells showed high expression of Mmp1 (Fig. 4E), which is known to be activated in Drosophila ensheathing glia upon brain injury (41). The injury-activated glia, despite comprising only 2.8% of total cells, was responsible for 44% of UMIs for Mmp1.…”

Section: Harpegnathos Ensheathing Glia Respond To Brain Injurymentioning

confidence: 94%

Social reprogramming in ants induces longevity-associated glia remodeling

et al. 2020

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In social insects, workers and queens arise from the same genome but display profound differences in behavior and longevity. In Harpegnathos saltator ants, adult workers can transition to a queen-like state called gamergate, which results in reprogramming of social behavior and life-span extension. Using single-cell RNA sequencing, we compared the distribution of neuronal and glial populations before and after the social transition. We found that the conversion of workers into gamergates resulted in the expansion of neuroprotective ensheathing glia. Brain injury assays revealed that activation of the damage response gene Mmp1 was weaker in old workers, where the relative frequency of ensheathing glia also declined. On the other hand, long-lived gamergates retained a larger fraction of ensheathing glia and the ability to mount a strong Mmp1 response to brain injury into old age. We also observed molecular and cellular changes suggestive of age-associated decline in ensheathing glia in Drosophila.

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A novel Drosophila injury model reveals severed axons are cleared through a Draper/MMP-1 signaling cascade

Cited by 59 publications

References 102 publications

Independent glial subtypes delay development and extend healthy lifespan upon reduced insulin-PI3K signalling

Independent glial subtypes delay development and extend healthy lifespan upon reduced insulin-PI3K signalling

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

Social reprogramming in ants induces longevity-associated glia remodeling

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