Abstract
Neuron glia antigen 2 (NG2)-positive glia are repair cells that proliferate upon central nervous system (CNS) damage, promoting functional recovery. However, repair is limited because of the failure of the newly produced glial cells to differentiate. It is a key goal to discover how to regulate NG2 to enable glial proliferation and differentiation conducive to repair. Drosophila has an NG2 homologue called kon-tiki (kon), of unknown CNS function. We show that kon promotes repair and identify the underlying mechanism. Crush injury up-regulates kon expression downstream of Notch. Kon in turn induces glial proliferation and initiates glial differentiation by activating glial genes and prospero (pros). Two negative feedback loops with Notch and Pros allow Kon to drive the homeostatic regulation required for repair. By modulating Kon levels in glia, we could prevent or promote CNS repair. Thus, the functional links between Kon, Notch, and Pros are essential for, and can drive, repair. Analogous mechanisms could promote CNS repair in mammals.
Highlights
Injury to the central nervous system (CNS) induces a glial regenerative response (GRR) that is evolutionarily conserved across animals, from flies to humans (Smith et al, 1987; Franklin and ffrench-Constant, 2008; Kato et al, 2011)
Neuron glia antigen 2 (NG2)+ oligodendrocyte progenitor cells (OPCs) maintain CNS integrity and homeostasis: They interact closely with synapses; express factors involved in neurotransmitter recycling and neurotransmitter receptors; are the main CNS cell population to continuously divide throughout life; produce trophic factors that sustain neuronal survival; and are the progenitor cells for oligodendrocytes (OLs) that myelinate CNS axons
We have shown that the Drosophila NG2 homologue kon is expressed and required in neuropil glial (NG) for glial proliferation, activation, and onset of glial differentiation and is necessary and sufficient for CNS injury repair
Summary
Injury to the central nervous system (CNS) induces a glial regenerative response (GRR) that is evolutionarily conserved across animals, from flies to humans (Smith et al, 1987; Franklin and ffrench-Constant, 2008; Kato et al, 2011). The number of NG glial cells increased when kon was overexpressed in glia (repoGAL4>UASkon), as detected with Ebony, a downstream target of Pros and marker for the AlrmGAL4+ NG (Griffiths and Hidalgo, 2004; Kato et al, 2011; Peco et al, 2016; Fig. 2 e). These data suggest that Kon is required for and can induce glial proliferation, including of NG cells. These data demonstrate that Kon is required in NG for, and can promote, CNS repair
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