Cytoskeletal function in neuronal development and degeneration

The cytoskeleton is the internal scaffold of every cell; it provides mechanical support but is also required for cells to move. However it is more than just a static structure, it is highly dynamic and in a constant state of flux. Imagine a sprinter, the strength of their skeleton is a key factor in generating speed. Now consider what would happen if in addition to moving their bones, they could extend and contract those bones at will (roll the mouse over the skeleton). Extensible limbs would be a much bigger advantage than any dodgy dietary supplement.

Appropriate regulation of the neuronal cytoskeleton is critical for correct development of the nervous system and its maintenance throughout life. Similarly, mutations in axon guidance factors cause congenital human nervous system malformations and such proteins are increasingly implicated in neurodegenerative conditions. How guidance cues are linked to the cytoskeleton to direct migration is still poorly understood yet this is essential for understanding how the brain is wired up and how connections deteriorate during ageing. Our preliminary data place the actin-binding protein drebrin central to the co-ordination of cytoskeletal regulation with axon guidance receptor signalling.

Steering growing neurons

Growing axons are led to their destination by a highly specialised structure at the tip, called the growth cone (see Anatomy of a neuron). Protein receptors on the growth cone surface bind to other proteins produced by the tissue surrounding the neuron, these act in combination as positive and negative guidance signals to steer the growth cone towards its target. These biochemical cues must be converted into physical changes in the growth cone cytoskeleton in order. The dynamic nature of the cytoskeleton arises from the continual fraying, unravelling and regrowth of the microtubule and actin filaments. In response to a growth promoting signal the rate of incorporation of tubulin subunits at the microtubule tips increases leading to their extension and thus of the axon also. The addition of actin monomers into the polymer filaments can be stimulated likewise. Conversely, negative cues that repel a growth cone trigger local disassembly of microtubules and actin.
A host of proteins either directly or indirectly regulate the state of cytoskeleton and its precarious balance between growth and collapse known as a 'dynamic equilibrium'. Drebrin binds to actin filaments that have already been formed and stabilises them by gathering them into bundles which tends to protect them against depolymerisation. Such bundles are the core of filopodia, the finger-like projections around the edge of growth cones; indeed filopodia are believed to be key to cell migration and are the subject of extensive study to understand the spread of cancer cells. Genetically elevating the amount of drebrin in a cell induces the formation of longer, more numerous filopodia; removing it entirely from growth cones causes them to completely collapse.

Drebrin and disease

Drebrin has a potent ability to change the shape of neurons. This important role carries on beyond development into the adult brain - the tips of the axon form the contacts (synapses) with target cells. Disrupting the ability of these structures to respond to enviromental cues and modulate their form is required for the release and reception of neurotransmitters, the formation and strength of connections. In short, it will have profound effects on nervous communication. This is underscored by the loss of drebrin associated with Down Syndrome and Alzheimer Disease. For a more thorough account of the links between drebrin and disease see Dun and Chilton (2010).

Drebrin regulates neuronal migration and axon morphology

To address the role of drebrin in neuronal migration and axon guidance we use the embryonic chick oculomotor system. This is an excellent model: we have defined its development in detail and successfully used it to investigate human dysinnervation disorders. Drebrin is necessary for the formation of neurites, the long processes that will become axons and dendrites and it potently induces filopodia in neurons and indeed other cell types. Drebrin is enriched in the leading processes of oculomotor neurons, this is a specialised structure, similar to an axonal growth cone, which guides migrating neurons to their correct location in the developing brain. If we genetically inhibit drebrin expression this blocks process formation and cell migration. Conversely, genetically increasing the amount of drebrin – or introducing a mutated form with increased propensity to form filopodia - induces precocious migration of oculomotor neurons along a dramatically deviated pathway, implying altered responses to environmental guidance cues. When we first discovered this effect, it was a bit like adjusting a car's motor only to find that it still goes but the steering no longer works. This strongly supports our hypothesis that drebrin is not simply required for process formation but for the interpretation of navigational signals.

Other research topics:
References

Dun XP, Chilton JK. (2010) Control of cell shape and plasticity during development and disease by the actin-binding protein Drebrin.
Histol Histopathol. 25(4):533-40 PubMed