Abstract
ABSTRACTThe mammalian central nervous system (CNS) exhibits limited regenerative capacity and the mechanisms that mediate its regeneration are not fully understood. Here, we present a novel experimental design to damage the CNS by using a contusion injury paradigm. The design of this protocol allows the study of long-term and short-term cellular responses, including those of the CNS and the immune system, and of any implications regarding functional recovery. We demonstrate for the first time that adult Drosophila melanogaster glial cells undergo spontaneous functional recovery following crush injury. This crush injury leads to an intermediate level of functional recovery after damage, which is ideal to screen for genes that facilitate or prevent the regeneration process. Here, we validate this model and analyse the immune responses of glial cells as a central regulator of functional regeneration. Additionally, we demonstrate that glial cells and macrophages contribute to functional regeneration through mechanisms involving the Jun N-terminal kinase (JNK) pathway and the Drosophila protein Draper (Drpr), characteristic of other neural injury paradigms. We show that macrophages are recruited to the injury site and are required for functional recovery. Further, we show that the proteins Grindelwald and Drpr in Drosophila glial cells mediate activation of JNK, and that expression of drpr is dependent on JNK activation. Finally, we link neuron-glial communication and the requirement of neuronal vesicular transport to regulation of the JNK pathway and functional recovery.This article has an associated First Person interview with the first author of the paper.
Highlights
Mammalian central nervous system (CNS) has limited regenerative capacity in contrast to the peripheral nervous system (PNS) (Curcio and Bradke, 2018)
This crush injury leads to an intermediate level of functional recovery after damage, which is ideal to screen for genes that facilitate or prevent the regeneration process
We demonstrate that glia and macrophages contribute to functional regeneration through mechanisms involving the c-Jun N-terminal kinase (JNK) pathway and Draper, characteristic of other neural injury paradigms
Summary
Mammalian central nervous system (CNS) has limited regenerative capacity in contrast to the peripheral nervous system (PNS) (Curcio and Bradke, 2018). The limited regenerative capacity of neurons, myelin associated inhibitory factors and the presence of glial scar, restrict regeneration in the mammalian CNS (Cregg et al, 2014; Silver and Miller, 2004) Other vertebrates such as zebrafish, undergo spontaneous regeneration of the PNS and CNS following injury; facilitating functional recovery (Rasmussen and Sagasti, 2017). Other injury models as axon regeneration following laser ablation have emerged as suitable models to investigate the cellular properties of regeneration (Stone et al, 2010; Yanik et al, 2004) This model has contributed to uncover the implication of microtubules (Chen et al, 2011), dendrite-axon interconversion (Stone et al, 2010), and the decline of spontaneous functional recovery with age (Byrne et al, 2014). Whilst these mechanisms are conserved in mammals, they do not participate in CNS regeneration (Curcio and Bradke, 2018)
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