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PI3K signaling and Stat92E converge to modulate glial responsiveness to axonal injury.

Doherty J, Sheehan AE, Bradshaw R, Fox AN, Lu TY, Freeman MR - PLoS Biol. (2014)

Bottom Line: Surprisingly, canonical JAK/STAT signaling does not regulate draper expression.Rather, we find injury-induced draper activation is downstream of the Draper/Src42a/Shark/Rac1 engulfment signaling pathway.We provide evidence for a positive auto-regulatory mechanism whereby signaling through the injury-responsive Draper receptor leads to Stat92E-dependent, transcriptional activation of the draper gene.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurobiology, Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.

ABSTRACT
Glial cells are exquisitely sensitive to neuronal injury but mechanisms by which glia establish competence to respond to injury, continuously gauge neuronal health, and rapidly activate reactive responses remain poorly defined. Here, we show glial PI3K signaling in the uninjured brain regulates baseline levels of Draper, a receptor essential for Drosophila glia to sense and respond to axonal injury. After injury, Draper levels are up-regulated through a Stat92E-modulated, injury-responsive enhancer element within the draper gene. Surprisingly, canonical JAK/STAT signaling does not regulate draper expression. Rather, we find injury-induced draper activation is downstream of the Draper/Src42a/Shark/Rac1 engulfment signaling pathway. Thus, PI3K signaling and Stat92E are critical in vivo regulators of glial responsiveness to axonal injury. We provide evidence for a positive auto-regulatory mechanism whereby signaling through the injury-responsive Draper receptor leads to Stat92E-dependent, transcriptional activation of the draper gene. We propose that Drosophila glia use this auto-regulatory loop as a mechanism to adjust their reactive state following injury.

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Related in: MedlinePlus

Basal and injury-induced Draper expression are regulated through two distinct pathways.Basal levels of Draper expression are dependent upon the convergent activities of PI3K and Stat92E signaling. After injury Draper signals through the Src family kinase signaling cascade (Src and Shark), and Rac1, and transcriptionally activates its own expression in a Stat92e-dependent fashion. Increased levels of Draper (and perhaps other engulfment genes) likely enhance the ability of glia to engulf axonal debris.
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pbio-1001985-g007: Basal and injury-induced Draper expression are regulated through two distinct pathways.Basal levels of Draper expression are dependent upon the convergent activities of PI3K and Stat92E signaling. After injury Draper signals through the Src family kinase signaling cascade (Src and Shark), and Rac1, and transcriptionally activates its own expression in a Stat92e-dependent fashion. Increased levels of Draper (and perhaps other engulfment genes) likely enhance the ability of glia to engulf axonal debris.

Mentions: In mammals, it is widely accepted that reactive glial responses are graded according to the severity of the brain injury. Here we show that Drosophila glia also respond in a graded way to ORN injury: axotomy of a small number of ORN axons by maxillary palp ablation led to dee7-Gal4 activity in a small subset of cells, while severing the majority of ORNs (∼85%) by antennal ablation led to a more dramatic increase in the activation of two separate reporters. We propose that relatively mild injuries promote signaling through the Draper pathway in a limited number of cells close to the site of injury while more severe injuries result in widespread activation of the Draper pathway in cells throughout the entire brain, even those distant from the injury site. Presumably up-regulation of engulfment factors enhances the ability of glia to clear neuronal debris (Figure 7). Such a mechanism whereby glial transcriptional responses are activated downstream of the very pathways that drive glial phagocytic activity would allow glia to directly modulate their engulfment capacity. Since it is likely that Draper ligands are present on engulfment targets, transcriptional activation of glial engulfment genes would ultimately be regulated by extracellular levels of “eat me” cues on degenerating axons.


PI3K signaling and Stat92E converge to modulate glial responsiveness to axonal injury.

Doherty J, Sheehan AE, Bradshaw R, Fox AN, Lu TY, Freeman MR - PLoS Biol. (2014)

Basal and injury-induced Draper expression are regulated through two distinct pathways.Basal levels of Draper expression are dependent upon the convergent activities of PI3K and Stat92E signaling. After injury Draper signals through the Src family kinase signaling cascade (Src and Shark), and Rac1, and transcriptionally activates its own expression in a Stat92e-dependent fashion. Increased levels of Draper (and perhaps other engulfment genes) likely enhance the ability of glia to engulf axonal debris.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4219656&req=5

pbio-1001985-g007: Basal and injury-induced Draper expression are regulated through two distinct pathways.Basal levels of Draper expression are dependent upon the convergent activities of PI3K and Stat92E signaling. After injury Draper signals through the Src family kinase signaling cascade (Src and Shark), and Rac1, and transcriptionally activates its own expression in a Stat92e-dependent fashion. Increased levels of Draper (and perhaps other engulfment genes) likely enhance the ability of glia to engulf axonal debris.
Mentions: In mammals, it is widely accepted that reactive glial responses are graded according to the severity of the brain injury. Here we show that Drosophila glia also respond in a graded way to ORN injury: axotomy of a small number of ORN axons by maxillary palp ablation led to dee7-Gal4 activity in a small subset of cells, while severing the majority of ORNs (∼85%) by antennal ablation led to a more dramatic increase in the activation of two separate reporters. We propose that relatively mild injuries promote signaling through the Draper pathway in a limited number of cells close to the site of injury while more severe injuries result in widespread activation of the Draper pathway in cells throughout the entire brain, even those distant from the injury site. Presumably up-regulation of engulfment factors enhances the ability of glia to clear neuronal debris (Figure 7). Such a mechanism whereby glial transcriptional responses are activated downstream of the very pathways that drive glial phagocytic activity would allow glia to directly modulate their engulfment capacity. Since it is likely that Draper ligands are present on engulfment targets, transcriptional activation of glial engulfment genes would ultimately be regulated by extracellular levels of “eat me” cues on degenerating axons.

Bottom Line: Surprisingly, canonical JAK/STAT signaling does not regulate draper expression.Rather, we find injury-induced draper activation is downstream of the Draper/Src42a/Shark/Rac1 engulfment signaling pathway.We provide evidence for a positive auto-regulatory mechanism whereby signaling through the injury-responsive Draper receptor leads to Stat92E-dependent, transcriptional activation of the draper gene.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurobiology, Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.

ABSTRACT
Glial cells are exquisitely sensitive to neuronal injury but mechanisms by which glia establish competence to respond to injury, continuously gauge neuronal health, and rapidly activate reactive responses remain poorly defined. Here, we show glial PI3K signaling in the uninjured brain regulates baseline levels of Draper, a receptor essential for Drosophila glia to sense and respond to axonal injury. After injury, Draper levels are up-regulated through a Stat92E-modulated, injury-responsive enhancer element within the draper gene. Surprisingly, canonical JAK/STAT signaling does not regulate draper expression. Rather, we find injury-induced draper activation is downstream of the Draper/Src42a/Shark/Rac1 engulfment signaling pathway. Thus, PI3K signaling and Stat92E are critical in vivo regulators of glial responsiveness to axonal injury. We provide evidence for a positive auto-regulatory mechanism whereby signaling through the injury-responsive Draper receptor leads to Stat92E-dependent, transcriptional activation of the draper gene. We propose that Drosophila glia use this auto-regulatory loop as a mechanism to adjust their reactive state following injury.

Show MeSH
Related in: MedlinePlus