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Regulation of PTEN activity during growth cone motility and guidance

Reference	BB/C514307/1
Principal Investigator / Supervisor	Professor Britta Eickholt
Co-Investigators / Co-Supervisors	Dr Neil Chadborn
Institution	King's College London
Department	Molecular Neurobiology Group
Funding type	Research
Value (£)	249,321
Status	Completed
Type	Research Grant
Start date	01/09/2005
End date	31/08/2008
Duration	36 months

Abstract

In the adult central nervous system, the intrinsic ability to regenerate an injured axon is prevented by the inhibitory environment presented by the surrounding myelin, and also largely by the absence of limited levels of factors promoting growth and survival factors. Thus, the capacity to induce regeneration depends on the ability to promote growth and/or to overcome inhibitory influences. In recent years several key signalling pathways involved in modulating both stimulation and inhibition of neuronal outgrowth have been identified, one of which is the PI 3-kinase signalling pathway. Activation of PI 3-kinases results in the production of phosphatidylinositol-3,4,5-trisphospate (PIP3), and through protein effectors containing pleckstrin homology (PH) domains, PIP3 is known to modulate cytoskeletal rearrangement leading to changes in cellular motility. Levels of PIP3 are additionally controlled through dephosphorylation by a PI 3-phosphatase activity, which is mediated by the tumour suppressor PTEN. Whilst we know a considerable amount concerning the production of PIP3 through PI 3-kinases in neurons, our understanding of PTEN in similar processes is limited. We have recently shown that during the characteristic cycle of lamellipodia expansion and retraction of neuronal growth cone domains, PL 3-kinase activity was transiently localised to the expanding lamellipodium, whilst PTEN, the negative regulator of this pathway, was found at the rear of the cone. Sema3A, an inhibitor of axonal growth known to induce rapid growth cone collapse, suppressed Pl 3-kinase signalling concomitantly with an activation of GSK3 in growth cones. Upon acute exposure with Sema3A in neurons, PTEN rapidly accumulates in the growth cone, indicating a mechanism by which PTEN couples Sema3A signalling to characteristic morphological changes in neurons. These findings provided evidence for a function of PTEN to mediate specific aspects in growth cone function. We now propose to determine the mechanisms of PTEN regulation during normal growth cone motility and Sema3A mediated growth cone collapse. We also propose to instigate a study addressing the sub-cellular localisation of PTEN in neurons that may lead to the identification of novel neuronal binding partners for PTEN.

Summary

unavailable

Committee	Closed Committee - Biochemistry & Cell Biology (BCB)
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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