Author SummaryThe process of tissue regeneration has long been studied as a route to understanding what promotes structural robustness of cellular networks in animals. In the central nervous system (CNS), neurons and glia interact throughout adult life and during learning, at the same time accommodating functional changes while preserving the structural integrity necessary for function. The mechanisms that confer this combination of structural robustness and functional plasticity in the CNS are unknown, but they may be shared with the cellular responses to injury, which also require structural changes while retaining function. The glial cells that enwrap axons respond to injury by dividing and re-enwrapping them, leading to partial recovery of function. Here, we use Drosophila genetics to uncover a gene network underlying this glial regenerative response. This gene network enables glia to divide upon injury, prevent uncontrolled proliferation, and differentiate. We find that the network also has homeostatic properties: two cell-cycle activators (Notch and NFκB) promote the expression of a cell cycle inhibitor (Pros), providing negative feedback on cell division. Pros is also essential for glial differentiation, enabling the clearance of cellular debris and axonal enwrapment, and priming glia for further responses. By removing these genes or adding them in excess, we can shift the response to injury from prevention to promotion of lesion repair. This gene network is thus a homeostatic mechanism for structural robustness. Our findings from Drosophila may also help manipulation of glia to repair the damaged human CNS.