Astrocytes engage unique molecular programs to engulf pruned neuronal debris from distinct subsets of neurons

Abstract

Precise neural circuit assembly is achieved by initial overproduction of neurons and synapses, followed by refinement through elimination of exuberant neurons and synapses. Glial cells are the primary cells responsible for clearing neuronal debris, but the cellular and molecular basis of glial pruning is poorly defined. Here we show that Drosophila larval astrocytes transform into phagocytes through activation of a cell-autonomous, steroiddependent program at the initiation of metamorphosis and are the primary phagocytic cell type in the pupal neuropil. We examined the developmental elimination of two neuron populations-mushroom body (MB) g neurons and vCrz + neurons (expressing Corazonin [Crz] neuropeptide in the ventral nerve cord [VNC])-where only neurites are pruned or entire cells are eliminated, respectively. We found that MB g axons are engulfed by astrocytes using the Draper and Crk/Mbc/dCed-12 signaling pathways in a partially redundant manner. In contrast, while elimination of vCrz + cell bodies requires Draper, elimination of vCrz + neurites is mediated by Crk/Mbc/dCed-12 but not Draper. Intriguingly, we also found that elimination of Draper delayed vCrz + neurite degeneration, suggesting that glia promote neurite destruction through engulfment signaling. This study identifies a novel role for astrocytes in the clearance of synaptic and neuronal debris and for Crk/Mbc/dCed-12 as a new glial pathway mediating pruning and reveals, unexpectedly, that the engulfment signaling pathways engaged by glia depend on whether neuronal debris was generated through cell death or local pruning.

DrosophilaCentral Nervous System Glia

“…2) (Awasaki et al 2008;Doherty et al 2009;Muthukumar et al 2014;Stork et al 2014;Tasdemir-Yilmaz and Freeman 2014). Of the three glial subtypes discussed in this chapter astrocytes by far are the most heavily studied.…”

“…However, within 6 h after puparium formation (APF) steroid-dependent signaling events in astrocytes result in their dramatic increase Draper expression, transformation into phagocytes, and initiation of engulfment of pruned axons, dendrites, and synapses (Tasdemir-Yilmaz and Freeman 2014). Blockade of signaling through the ecdysone receptor, or Draper, suppresses axon clearance of MB g neurons (Hakim et al 2014;Tasdemir-Yilmaz and Freeman 2014). Surprisingly, careful genetic studies reveal that there is not a single engulfment pathway responsible for clearance of all neurite debris during pruning.…”

“…In contrast, it appears that astrocytes engage unique molecular programs to engulf different subsets of neurites. For instance, clearance of MB g neuron axons requires Draper signaling (Awasaki et al 2006;Hoopfer et al 2006;Hakim et al 2014;Tasdemir-Yilmaz and Freeman 2014) and the guanine nucleotide exchange factor (GEF) Crk/Mbc/ dCed12 in a partially redundant fashion . In contrast, the clearance of neurites from ventral corazonin expressing (vCrz þ ) neurons requires Crk/Mbc/ dCed12, although Draper is completely dispensable (Tasdemir-Yilmaz and Freeman 2014).…”

Microglia in steady state

“…Several studies indicate that microglia play a major role in synaptic pruning of neurons, and we are only starting to understand the detailed mechanisms of this process. More research is needed to further elucidate the role of the synaptic pruning performed by microglial cells compared with synaptic pruning seen in other glial cells such as astrocytes and self-pruning of neurons (70)(71)(72)(73).…”

Glial cells in neuronal development: recent advances and insights from Drosophila melanogaster

“…A Wallerian degeneration process has recently been well exemplifi ed in Drosophila olfactory receptor neurons [79] and it has been shown that draper expression is similarly upregulated when axons undergo injury in this model [79][80][81][82] . Yet, unlike γ-axon pruning where astrocyte-like glia are the major subtype responsible [75,83] , ensheathing glia have been shown to engulf debris during axon injury of olfactory receptor neurons [84] (Fig. 4B).…”