Award details

Drebrin function in growth cones

Reference	BB/H010963/1
Principal Investigator / Supervisor	Professor Phillip Gordon-Weeks
Co-Investigators / Co-Supervisors
Institution	King's College London
Department	MRC Ctr for Developmental Neurobiology
Funding type	Research
Value (£)	650,282
Status	Completed
Type	Research Grant
Start date	10/05/2010
End date	09/05/2013
Duration	36 months

Abstract

Interactions between dynamic microtubules and actin filaments are known to be crucial for neuritogenesis and growth cone pathfinding in differentiating neurons. However, the molecular components underlying this interaction and how it is regulated are unknown. We have recently shown that the microtubule +TIP protein EB3, located on the growing ends of dynamic microtubules, binds directly to the actin-binding protein drebrin in the proximal region of growth cone filopodia. We hypothesize that this binding is at the centre of the molecular machinery that mediates the coupling of microtubules and F-actin that underlies neuritogenesis and growth cone pathfinding (Geraldo et al., 2008). The overall aim of this proposal is to identify the functional roles that drebrin plays in neuritogenesis and growth cone pathfinding. We will define the F-actin-binding domains and the EB3 binding site on drebrin and investigate the role of tyrosine phosphorylation of drebrin in regulating its interactions with F-actin and EB3. This information will lead to the derivation of dominant negative deletion and point-mutation constructs that will be used, along with small molecule inhibitors, in functional studies of neuritogenesis and growth cone pathfinding of cultured embryonic cortical neurons. These experiments are designed to further our understanding of microtubule/F-actin interactions in growth cones and have implications for understanding the molecular mechanisms underlying neuritogenesis and growth cone pathfinding at a molecular level. Interactions between dynamic microtubules and F-actin underlie a range of cellular processes including cell polarity, cell division and directed cell motility and recent evidence suggests that these interactions are also important for dendritic spine plasticity. The studies proposed here will therefore have a wide impact.

Summary

The proper functioning of the nervous system depends on nerve cells forming appropriate connections with each other during embryonic development. Nerve cells form connections in the embryo by extending fine processes called neurites at the tip of which is a motile structure called a growth cone that masterminds the search in the embryo for a connecting cell. The growth cone is guided by signals from other cells and responds to these by changes in growth. The formation and growth of neurites and their growth cones involves the building of a skeleton (cytoskeleton) to provide structural support. The cytoskeleton is a dynamic structure continually changing in response to guidance signals. The research proposed will improve our understanding of how the cytoskeleton enables growth cone movement under the influence of guidance signals to occur properly. In particular, we will learn how two important classes of filaments, microtubules and microfilaments, that form the cytoskeleton of neurites and growth cones, interact with each other. This research will not only help us to understand a fundamental process in nervous system development but it will also contribute to the effort to repair nervous systems in humans that do not develop properly or become damaged.

Impact Summary

The discovery, by Avery August's group, that drebrin is an intracellular target of the immunosuppressant BTP2 (YM-58483) identifies a new intracellular pathway in the immune response and has considerable potential for the development of novel immunosuppressants. Drebrin presumably plays some part in the coupling between the efflux of Ca2+ from the endoplasmic reticulum stores and the influx of Ca2+ through store-operated Ca2+ channels in the plasma membrane, though this has yet to be shown. Discovering the molecular details of this pathway is likely to identify novel drug targets for immunosuppression and would be of considerable interest to the pharmaceutical industry. We are currently collaborating with August's group in this area. There is a decline in dendritic drebrin levels in the brains of people with mild cognitive impairment, in Alzheimer's patients and in transgenic mouse models of Alzheimer's. Expression levels of drebrin A correlate directly with the severity of cognitive impairment, since people with mild cognitive impairment exhibit decreased drebrin levels in comparison to control groups, with a further decrease in drebrin content in individuals with Alzheimer's. Although it is not clear whether loss of drebrin is causal to spine loss or a consequence of it, research on the basic molecular biology of drebrin and in particular its interaction with F-actin is likely to impact on dendritic spine synaptic plasticity and hence cognitive impairment. Polyclonal antibodies, dominant negative constructs and other reagents generated by the research programme have commercial value. We have a long-standing relationship with SeroTec who have marketed our antibodies in the past. The four phospho-tyrosine antibodies that will be raised during the programme may be suitable for marketing.

Committee	Research Committee D (Molecules, cells and industrial biotechnology)
Research Topics	Neuroscience and Behaviour
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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