Glial phagocytosis in developing and mature Drosophila CNS: tight regulation for a healthy brain

Hilu‐Dadia, Reut; Kurant, Estee

doi:10.1016/j.coi.2019.11.010

Cited by 23 publications

(24 citation statements)

References 54 publications

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“…Why do multiple PS-receptors drive engulfment across glia? Further, while we identified PSR-1 and integrins, other PS-receptors identified in glial pruning include CED-1/MEGF10/Draper, MerTK and GPR56 as well as yet-unidentified receptors (Chung et al, 2013; Freeman, 2015; Hilu-Dadia and Kurant, 2020; Kevany and Palczewski, 2010; Li et al, 2020; Nomura-Komoike et al, 2020; Tasdemir-Yilmaz and Freeman, 2014; Vecino et al, 2016). We speculate that PS-receptor diversity might imply functional heterogeneity in glial engulfment across context.…”

Section: Discussionmentioning

confidence: 81%

Glia actively sculpt sensory neurons by controlled phagocytosis to tune animal behavior

Raiders

Black

Bae

et al. 2020

Preprint

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Glia in the central nervous system engulf neuron fragments during synapse remodeling and recycling of photoreceptor outer-segments. Whether glia passively clear shed neuronal debris, or actively remove neuron fragments is unknown. How pruning of single-neuron endings impacts animal behavior is also unclear. Here we report that adult C. elegans AMsh glia engulf sensory endings of the AFD thermosensory neuron. Engulfment is regulated by temperature, AFD’s sensory input, and tracks AFD activity. Phosphatidylserine (PS) flippase TAT-1/ATP8A, functions with glial PS-receptor PSR-1/PSR and PAT-2/α-integrin to initiate engulfment. Glial CED-10/Rac1 GTPase, acting through a conserved GEF complex, executes phagocytosis using the actin-remodeler WSP-1/nWASp and the membrane-sealing factor EFF-1 fusogen. CED-10 levels determine engulfment rates, and engulfment-defective mutants exhibit altered AFD-ending shape and thermosensory behavior. Our findings reveal a molecular pathway underpinning glia-dependent phagocytosis in a peripheral sense-organ, and demonstrate that glia actively engulf neuron-fragments, with profound consequences on neuron shape and animal behavior.

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Section: Discussionmentioning

confidence: 81%

Glia actively sculpt sensory neurons by controlled phagocytosis to tune animal behavior

Raiders

Black

Bae

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…Neurons and glia are two major cell types in the nervous system of both vertebrate and invertebrate animals. Glial cells are critical for the development and function of neurons by providing neurons with survival and axonal guidance cues, electric shield, and acting as macrophages to remove injured/dead cells ( Yildirim et al 2019 ; Bittern et al 2020 ; Hilu-Dadia and Kurant 2020 ). Previous studies have shown that Notch signaling plays an important and evolutionarily conserved role in regulating glial differentiation and proliferation during development or following neuronal injuries ( Jacobs 2000 ; Hidalgo and Logan 2017 ; Kato et al 2018 ; Bahrampour and Thor 2020 ).…”

Section: Resultsmentioning

confidence: 99%

Genetic interactions regulate hypoxia tolerance conferred by activating Notch in excitatory amino acid transporter 1-positive glial cells inDrosophila melanogaster

Zhou

Stobdan

Visk

et al. 2021

G3 Genes|Genomes|Genetics

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Hypoxia is a critical pathological element in many human diseases, including ischemic stroke, myocardial infarction and solid tumors. Of particular significance and interest of ours are the cellular and molecular mechanisms that underlie susceptibility or tolerance to low O2. Previous studies have demonstrated that Notch signaling pathway regulates hypoxia tolerance in both Drosophila melanogaster and humans. However, the mechanisms mediating Notch-conferred hypoxia tolerance are largely unknown. In the current study, we delineate the evolutionarily conserved mechanisms underlying this hypoxia tolerant phenotype. We determined the role of a group of conserved genes that were obtained from a comparative genomic analysis of hypoxia-tolerant Drosophila melanogaster populations and human highlanders living at the high-altitude regions of the world (Tibetans, Ethiopians and Andeans). We developed a novel dual-UAS/Gal4 system that allows us to activate Notch signaling in the Eaat1-positive glial cells, which remarkably enhances hypoxia tolerance in Drosophila melanogaster, and, simultaneously, knock down a candidate gene in the same set of glial cells. Using this system, we discovered that the interactions between Notch signaling and bnl (fibroblast growth factor), croc (forkhead transcription factor C) or Mkk4 (mitogen-activated protein kinase kinase 4) are important for hypoxia tolerance, at least in part, through regulating neuronal development and survival under hypoxic conditions. Since these genetic mechanisms are evolutionarily conserved, this group of genes may serve as novel targets for developing therapeutic strategies and have a strong potential to be translated to humans to treat/prevent hypoxia-related diseases.

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“…Excess glial projections could, for example, reflect phagocytic behavior gone awry, given that wild type projections positively regulate synaptic arbor morphology through this mechanism (Fuentes-Medel et al, 2009). Indeed, these phagocytic engulfment events, mediated by the Draper receptor, have been shown to play both neuroprotective and neurodegenerative roles in the CNS, depending on context (reviewed in Logan, 2017;Hilu-Dadia and Kurant, 2019). Whether SPG projections in spastin mutants have analogous functions remains to be determined, however, particularly given the lack of correlation we observed between synaptic bouton and SPG morphologies at individual NMJs in both wild type and mutant animals.…”

Section: Discussionmentioning

confidence: 99%

Suppression of spastin Mutant Phenotypes by Pak3 Loss Implicates a Role for Reactive Glia in AD-HSP

et al. 2020

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Neurodegenerative mechanisms due to mutations in spastin currently center on neuronal defects, primarily in microtubule and endomembrane regulation. Spastin loss in Drosophila larvae compromises neuronal microtubule distribution, alters synaptic bouton morphology, and weakens synaptic transmission at glutamatergic neuromuscular junction (NMJ) synapses. Pak3, a p21-activated kinase that promotes actin polymerization and filopodial projections, is required for these spastin mutant defects; animals lacking both genes have normal NMJs. Here we show that Pak3 is expressed in central and peripheral glial populations, and reduction of Pak3 specifically in subperineurial glial cells is sufficient to suppress the phenotypes associated with spastin loss. Subperineurial glia in the periphery ensheathe motor neuron axons and have been shown to extend actin-based projections that regulate synaptic terminals during normal NMJ development. We find that these subperineurial glial projections are Pak3-dependent and nearly twice as frequent in spastin mutants, while in Pak3, spastin double mutants, neither glial projections nor synaptic defects are observed. Spastin deficiency thus increases Pak3-dependent subperineurial glia activity, which is in turn required for neuronal defects. Our results demonstrate a central role for Pak3-mediated, altered glial behavior in the neuronal defects due to spastin loss, and suggest that a similar reactive glia-mediated mechanism may underlie human AD-HSP pathogenesis.

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Glial phagocytosis in developing and mature Drosophila CNS: tight regulation for a healthy brain

Cited by 23 publications

References 54 publications

Glia actively sculpt sensory neurons by controlled phagocytosis to tune animal behavior

Glia actively sculpt sensory neurons by controlled phagocytosis to tune animal behavior

Genetic interactions regulate hypoxia tolerance conferred by activating Notch in excitatory amino acid transporter 1-positive glial cells inDrosophila melanogaster

Suppression of spastin Mutant Phenotypes by Pak3 Loss Implicates a Role for Reactive Glia in AD-HSP

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