Glia projects

Control of glial proliferation during neuronal circuit formation

Glial cell proliferation is coordinated with neural network formation. Glial cells are delivered sequentially, during events in which axons fasciculate or defasciculate, at different time points. In this way, the controlled delivery of glial cells sorts axonal patterns through time. We have also found that eliminating neurons causes a drop in glial division first, and an excess in glial proliferation later on, at times when glia do not normally divide. This latter over-proliferation mimics the repair response of vertebrate glia upon neuronal injury.

The gene Prospero couples glial proliferation to axon guidance. Prospero is present in all dividing longitudinal glia during axon guidance and subsequently in glia that remain as immature precursors with mitotic potential. This enables glial number adjustments in response to limited environmental changes during development. We are currently investigating further the molecular mechanisms underlying these plastic events.

Funded by: BBSRC studentship, The Wellcome Trust and EMBO YIP.

See Griffiths & Hidalgo 2004; Griffiths et al 2007.

Gliatrophic factors: Neuregulin and PVF

We have shown that the control of neuronal and glial cell survival is a more ancient mechanism than previously thought, conferring plasticity to nervous system development also in invertebrates. Two of the main gliatrophic factors in vertebrates are Neuregulin and PDGF. Drosophila glia number is regulated by the non-autonomous control of cell survival, using these conserved molecular pathways: (1) Targeted neuronal ablation results in an increase in glial apoptosis. The Drosophila Neuregulin homologue, called Vein, is produced by neurons and regulates the survival of a subset of the longitudinal glia via the Ras/MAPKinase/ERK pathway. This was the first evidence of a conserved gliatrophic factor from vertebrates to flies. (2) The PVF/PVR signalling pathway regulates midline glial survival and migration in Drosophila, via the P13K/Akt pathway. This is likely to be redundant with the EGF pathway, which has been well documented by others to promote midline glia survival. The effects on cell number can be more subtle in fruit-flies compared to vertebrates, but the mechanisms are conserved and influence axon guidance.

Funded by: MRC studentship, The Wellcome Trust, MRC CEG and EMBO YIP.

See Learte et al 2008; Hidalgo et al 2001; Kinrade et al 2001; and several reviews.

Glial cells in axon guidance

Glia had long been proposed to function as guidepost cells during axon guidance. We tested this idea in Drosophila, using targeted genetic ablation of very small numbers of glial cells at a time, and looking also at mutants lacking the gcm gene which is necessary for normal glial development. We showed that in the central nervous system (CNS) longitudinal glial cells migrate together with but ahead of the extending growth cones, and project large lamellipodia that explore the territory ahead of the growth cones. Glia occupy choice positions that guide axon guidance decisions by pioneer neurons. Targeted genetic ablation of glial cells alters axonal fasciculation and growth cone steering at choice points. Defects in glial cells upon loss of the glial gene gcm also results in axon guidance defects. We thus demonstrated that glial cells play important roles during axon guidance, orienting growth cones and triggering fasciculation and defasciculation decisions at choice points.

Funded by: The Wellcome Trust.

See Hidalgo and Booth 2000; Kinrade et al 2001; Learte & Hidalgo 2007.

The gene network underlying the glial regenerative response to central nervous system injury

We have discovered a gene network that confers structural robustness and plasticity to the normal central nervous system, and enables repair upon injury. For this, we established an injury paradigm in the Drosophila larval ventral nerve cord. The gene network comprises two feedback loops, one involving the genes Prospero (Pros) and Notch, and the second one involving Pros and NFκB. This gene network enables glia to divide upon injury, restore arrest preventing uncontrolled proliferation, and differentiate. It has homeostatic properties as 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 debris clearance and axonal enwrapment, and priming glia for further responses. By removing these genes or adding them in excess, we shifted from prevention to promotion of lesion repair. This gene network is a homeostatic mechanism for structural robustness. It may also help manipulation of glia to repair the damaged human CNS.

Funded by: EU Marie Curie International Incoming Post-doctoral Fellowship, Royal Society and Yamada Science Foundation Short Visit Fellowships and BBSRC Project Grant.

See Kato, Forero, Fenton and Hidalgo (2011) PLoS Biology 9, e1001133.