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

Abstract

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.

Drosophila glia: Few cell types and many conserved functions

“…Glial cells also aid regenerative responses in the Drosophila nervous system. For example, ensheathing glial cells are responsible to clear axonal debris after acute axotomy in the antenna or wing which requires Insulin receptor, Draper and MMP-1 activities (Doherty et al, 2009;Musashe, Purice, Speese, Doherty, & Logan, 2016;Purice et al, 2017). In Drosophila larvae it was shown that injury also promotes the proliferation of Prospero expressing astrocyte-like glial cells (Kato, Forero, Fenton, & Hidalgo, 2011).…”

Adipokines set neural tone by regulating synapse number

“…In all three manipulations, we observed increased systemic TAG, confirming that Insulin signaling functions in STAT-expressing cells to restrict fat storage. To identify expression of InR within the PI-STAT neurons, we made use of an antibody against human phosphorylated InR, and previously shown to cross-react with Drosophila InR (Musashe et al, 2016). We detected InR expression 20 in the somas of GFP-marked PI-STAT neurons (STAT-Gal4>UAS-tdGFP) ( Figure 7D, arrows), supporting a potential role for Insulin signaling in the restriction of systemic fat storage through regulation of PI-STAT neuron activity.…”

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

“…In all species, this class of receptors initiates a highly conserved canonical cascade that includes PI3K (35). Recent work has revealed a unique role for the insulin-like pathway in the context of glial immune responses to nerve injury in adult flies (36*). 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*).…”

“…Recent work has revealed a unique role for the insulin-like pathway in the context of glial immune responses to nerve injury in adult flies (36*). 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. Importantly, forced expression of Draper in glial-InR depleted flies provides significant rescue with regard to axon engulfment, indicating that the insulin-like pathway as an important upstream positive regulator of Draper and glial phagocytic function (36*). It is well established that systemic insulin-like signaling pathways gradually decline with age across species (37); future work will reveal if this contributes to age-related loss of Draper/MEGF10 and attenuated glial immune responses in older animals.…”