PI3K Signaling and Stat92E Converge to Modulate Glial Responsiveness to Axonal Injury

Doherty, Johnna E.; Sheehan, Amy E.; Bradshaw, Rachel; Fox, A. Nicole; Lu, Tsai-Yi; Freeman, Marc

doi:10.1371/journal.pbio.1001985

Cited by 60 publications

(112 citation statements)

References 87 publications

(96 reference statements)

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“…table S4). The Wg pathway includes naked cuticle [25] , sulfated [26] , shifted [27] , nemo [28] and Rho1 [29] , whereas the Jak/STAT signaling involves 2 members of the SOCS family [30] and a PI3-kinase (CG4141), which acts in a regulatory loop upon axonal injury [31] .…”

Section: Transcriptome Analysis Identifies Pathways That Are Regulatementioning

confidence: 99%

The Drosophila Chitinase-Like Protein IDGF3 Is Involved in Protection against Nematodes and in Wound Healing

et al. 2015

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required for the formation of hemolymph clots that seal wounds, and Idgf3 mutants display an extended developmental delay during wound healing. Altogether, our findings indicate that vertebrate and invertebrate CLP proteins function in analogous settings and have a broad impact on inflammatory reactions and infections. This opens the way to further genetic analysis of Drosophila IDGF3 and will help to elucidate the exact molecular context of CLP function.

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Section: Transcriptome Analysis Identifies Pathways That Are Regulatementioning

confidence: 99%

The Drosophila Chitinase-Like Protein IDGF3 Is Involved in Protection against Nematodes and in Wound Healing

et al. 2015

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“…Notably, conserved molecules essential for glial engulfment activity exist are conserved, including the Draper/MEGF10 receptor, which signals through a tyrosine based-activation motif (ITAM)/Src tyrosine kinase signaling cascade to regulate phagocytic removal of degenerating axons and apoptotic neurons (Chung et al, 2013; Logan et al, 2012; MacDonald et al, 2006; Scheib et al, 2012; Wu et al, 2009). In Drosophila , olfactory nerve axotomy triggers upregulation of Draper in local ensheathing glial cells, which is essential for efficient glial clearance of axonal debris (Doherty et al, 2014; Logan et al, 2012; MacDonald et al, 2006), but little is known about the upstream signals that trigger upregulation of Draper or other innate immune genes in responding glia.…”

Section: Introductionmentioning

confidence: 99%

Insulin-like Signaling Promotes Glial Phagocytic Clearance of Degenerating Axons through Regulation of Draper

et al. 2016

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Neuronal injury triggers robust responses from glial cells, including altered gene expression and enhanced phagocytic activity to ensure prompt removal of damaged neurons. The molecular underpinnings of glial responses to trauma remain unclear. Here, we find that the evolutionarily conserved Insulin-like signaling (ILS) pathway promotes glial phagocytic clearance of degenerating axons in adult Drosophila. We find that the Insulin-like Receptor (InR) and downstream effector Akt1 are acutely activated in local ensheathing glia after axotomy, and are required for proper clearance of axonal debris. InR/Akt1 activity is also essential for injury-induced activation of STAT92E and its transcriptional target draper, which encodes a conserved receptor essential for glial engulfment of degenerating axons. Increasing Draper levels in adult glia partially rescues delayed clearance of severed axons in glial InR-inhibited flies. We propose that ILS functions as a key post-injury communication relay to activate glial responses, including phagocytic activity.

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Section: Glia In the Context Of Healthy Aging And Acute Injurymentioning

confidence: 99%

“…Draper couples to several downstream signaling pathways via tyrosine kinases, including the c-Jun N-terminal kinase (JNK) cascade, to alter cytoskeletal remodeling, gene transcription, and phagocytic function in glial cells (27–29). In Drosophila , Draper is also required for glial engulfment of degenerating axons after acute nerve axotomy in adults (23, 27, 29, 30). Notably, neurodegeneration occurs in aged draper mutant animals (31, 32), and this phenotype is rescued by glial expression of target of rapamycin 1 (TORC1), one factor implicated in proper processing of phagocytosed material (32).…”

Section: Glia In the Context Of Healthy Aging And Acute Injurymentioning

confidence: 99%

“…Musashe and colleagues (2016) now show that transection of the olfactory nerves in flies triggers increased insulin-like signaling in local ensheathing glia, the glial subtype responsible for phagocytically clearing degenerating axons in the adult brain (36*). Ensheathing glia typically upregulate Draper as they infiltrate injury sites and engulf degenerating olfactory projections (23, 27, 30). Genetic inhibition of the insulin-like pathway in ensheathing glia blocks injury-induced Draper upregulation and delays clearance of severed projections.…”

Section: Glia In the Context Of Healthy Aging And Acute Injurymentioning

confidence: 99%

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Glial contributions to neuronal health and disease: new insights from Drosophila

Logan

2017

Current Opinion in Neurobiology

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Glial cells are essential for proper formation and maintenance of the nervous system. During development, glia keep neuronal cell numbers in check and ensure that mature neural circuits are appropriately sculpted by engulfing superfluous cells and projections. In the adult brain, glial cells offer metabolic sustenance and provide critical immune support in the face of acute and chronic challenges. Dysfunctional glial immune activity is believed to contribute to age-related cognitive decline, as well as neurodegenerative disease risk, but we still know surprisingly little about the specific molecular pathways that govern glia-neuron communication in the healthy or diseased brain. Drosophila offers a versatile in vivo model to explore the conserved molecular underpinnings of glial cell biology and glial cell contributions to brain function, health, and disease susceptibility. This review addresses recent findings describing how Drosophila glial cells influence neuronal activity in the adult fly brain to support optimal brain function and, importantly, highlights new insights into specific glial defects that may contribute to neuronal demise.

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PI3K Signaling and Stat92E Converge to Modulate Glial Responsiveness to Axonal Injury

Abstract: Activation of glial cells following axon injury is mediated by a positive feedback loop downstream of the glial phagocytic receptor Draper, allowing the strength of the response to match the severity of injury.

Cited by 60 publications

References 87 publications

The <b><i>Drosophila</i></b> Chitinase-Like Protein IDGF3 Is Involved in Protection against Nematodes and in Wound Healing

The <b><i>Drosophila</i></b> Chitinase-Like Protein IDGF3 Is Involved in Protection against Nematodes and in Wound Healing

Insulin-like Signaling Promotes Glial Phagocytic Clearance of Degenerating Axons through Regulation of Draper

Glial contributions to neuronal health and disease: new insights from Drosophila

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