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

Derek T Musashe,Maria D Purice,Sean D Speese,Johnna Doherty,Mary A Logan

doi:10.1016/j.celrep.2016.07.022

Derek T Musashe, Maria D Purice + Show 3 more

Open Access

https://doi.org/10.1016/j.celrep.2016.07.022

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Abstract

Neuronal injury triggers robust responses from glialcells, 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, it 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.

Highlights

Glial cells are highly sensitive to changes in neuronal health and respond swiftly to diverse forms of neural trauma
Glial insulin-like receptor (InR) Signaling Is Required for Glial Phagocytic Clearance of Severed Axons in the Adult Drosophila Brain In an ongoing in vivo screen to identify genes required for glial engulfment of degenerating axons (Table S1), we found that RNAi against the serine/threonine kinase Akt1 (UAS-Akt1RNAi) in adult glia inhibited glial clearance of severed olfactory receptor neuron axons
Consistent with our finding that insulin-like signaling (ILS) is required to upregulate draper in glia after axon injury, we found that activation of the 10XSTATdGFP reporter was largely inhibited 24 hr post-axotomy in adult (E) Quantification of phospho-Akt signal in dorsal antennal lobes after computationally segmenting to GFP

Summary

Introduction

Glial cells are highly sensitive to changes in neuronal health and respond swiftly to diverse forms of neural trauma. Acute injury triggers robust responses in glia, including altered gene expression, glial infiltration of damaged areas, and glial clearance of degenerating neurons through phagocytic engulfment (Logan and Freeman, 2007; MacDonald et al, 2006; Napoli and Neumann, 2009). Many of these reactive glial responses are neuroprotective. There is intense interest in elucidating the molecular and cellular features of glial immunity that govern how glia sense and respond to neuronal stress and damage, including the extrinsic injury cues that rapidly activate robust intrinsic immune response programs in glia

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