Molecular mechanism of CNS regeneration in Drosophila

The aim is to investigate the molecular mechanisms of central nervous system (CNS) regeneration, using the fruit-fly Drosophila as model organism. The CNS does not regenerate upon injury, leading to permanent disability, but damage and disease to the brain or spinal cord induce a limited regenerative response in glial cells, which if understood, could be harnessed to promote regeneration and repair. Glial cells of ensheathing cell lineages (which enwrap axons), divide, produce trophic factors that maintain neuronal survival, aid axonal re-growth and navigation, and re-enwrap axons, leading to limited recovery of behaviour. This response is evolutionarily conserved, from insects to humans, revealing an underlying a genetic mechanism. Understanding this mechanism is essential to control the proliferation and differentiation of stem and progenitor cells for therapeutic activation in vivo, and for cell transplantations.
Funded by BBSRC, the team of Dr Hidalgo discovered a gene network underlying the glial regenerative response. It involves the genes Notch and prospero (pros), and pros and NFkB, that together prime cells to respond to injury, enable a fast response and up-regulate the expression of kon-tiki (kon). And negative feedback that switches off kon, restores homeostasis and terminates the response to injury. Kon activates glial proliferation and differentiation onset, thus enabling glial regeneration; Pros inhibits proliferation, restoring homeostasis, and activates and maintains glial differentiation. In collaboration with mammalian experts, the Hidalgo team showed that this gene network is evolutionarily conserved in the mouse.
Still, how glial cells interact with neurons in response to injury is not understood.
Here we will ask: 1) why do neurons improve when glial cells regenerate? Is this driven by a neuronal ligand or receptor for glial kon? 2) Is NFkB activated in glia by Toll receptors?