Control of the actin cytoskeleton by PI3K/PTEN signalling during dendritic remodelling

This research is directed at understanding the mechanisms of the patterning of the nervous system. It focuses on the cellular mechanisms that are involved in the formation of the complex arrangement and interconnection of the neurons within this system. During the process of development, neurons extend neuronal processes, which seek out the cells that they need to establish connection with. Following contact with their target, synapses are assembled which allow the communication between neurons. Rather than being stable structures, synapses are dynamic and continuously undergo shape changes. These changes in shape are controlled by changes in the cytoskeleton, which mainly consists of actin filaments. Indeed, direct interference with the actin filaments blocks shape changes of the synapse and impairs neuronal communication. Through changes in intracellular lipid signalling, the phosphatase PTEN is known to alter the morphology of synapses. In fact, many neurological conditions are associated with a deregulation of this signalling pathway. What is not known, however, is how this signalling pathway controls changes of the actin cytoskeleton, leading to altered synapse shapes. This research will investigate the mechanisms that control the actin cytoskeleton during changes in lipid signalling.

A fundamental question in neuroscience concerns the mechanisms that control the establishment of appropriate connectivity in the brain. Neuronal signalling mediated by PI3K and the principle antagonist of PI3K, the lipid phosphatase PTEN, has been identified as a major regulator in this process. It is important for neuronal differentiation and migration, in addition to axonal and dendritic remodelling. Whilst we know a considerable amount concerning the function of PI 3-kinases in neurons, our understanding of PTEN is limited. This is somewhat surprising given that mutations in PTEN in humans are associated with high incidences of neurological symptoms, including epilepsy, autism and mental retardation, which may be a direct consequence of underlying changes in neuronal circuitry. Therefore, it is critical to gain understanding of the molecular mechanism of how PTEN signalling regulates neuronal connectivity. The regulation of PTEN in neurons is likely to involve proteins that are in association with the phosphatase. However, little is currently known about such regulatory proteins. To identify novel proteins that interact with the PTEN we applied proteomics to screen for binding partners in rat brain tissue. We recovered Drebrin, an actin binding protein highly enriched in dendritic spines, and known to control dendritic morphology. With this proposed research we would like to address the question of whether the association of PTEN with Drebrin governs essential processes during re-organisation of the actin cytoskeleton at the synapse.