The role of talin and vinculin in neuronal mechanosensing.

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During development, billions of neurons form long cellular extensions called axons, which find their way to specific target sites such as other neurons. Through these connections neurons form a highly organised network and transmit information in form of electrical and chemical signals that govern our organ functions. Neurons need to find specific targets not only during the development of the nervous system but also after injury, when they have to regrow through damaged tissue. Failure to reconnect often leads to severe health problems - for example, to date there is no treatment for recovering function after spinal cord injuries. Neuroscience has focused on chemical signals regulating growth and regrowth of neurons for decades, but we are still far from understanding why neurons in human brains and spinal cords do not regenerate.The environment in the brain alters enormously during development, normal ageing, injury and certain diseases. Brain tissue is extremely soft. However, it becomes stiffer during ageing (in men more than in women), and under pathological conditions it can change dramatically in structure and stiffness. Prominent examples are scarring after injury or stroke, and the formation of rigid plaques or tangles in diseases such as Alzheimer's. Neurons sense such mechanical changes in their environment and respond with drastic changes in their behaviour, as best illustrated by the failure of axons to regrow after spinal cord injury due to the presence of scars. Therefore, understanding how neurons respond to their mechanical environment is important if we want to get a step closer to treating, for example, spinal cord injuries.Neurons can feel the stiffness of their environment by exerting forces on it and probing its deformation. In order to transmit forces, they 'grab' neighbouring structures using special proteins, which are called integrins. These integrins not only bind to the environment of the cells but also connect to a skeleton inside the cells. This link is not direct but is regulated by components that couple or uncouple the two. We did some first experiments that suggest that two of these coupling proteins (which are called talin and vinculin) allow neurons to measure the stiffness of their environment, but how they do this is still unclear. In order to investigate how these proteins regulate the neuronal response to their mechanical environment, and to what extent they are involved in telling neurons where to grow, two laboratories in Manchester and Cambridge team up and combine their long-standing expertise with integrins, neurons and forces. The proposed research aims to (i) determine how talin and vinculin transmit mechanical information between the outside world and the inside skeleton, (ii) investigate their role in sensing stiffness differences in the environment of neurons and how this affects neuronal outgrowth and guidance, and (iii) understand how talin and vinculin interact with each other and with another protein named RIAM, which likely explains how mechanical signals control axon outgrowth and pathfinding. To reach our goals, we will not only use cutting edge microscopy, biophysics and molecular biology techniques but also develop new tools to mimic the mechanically altered environmental conditions that neurons encounter. Our results will be combined into a model that outlines and predicts how environmental signals and intracellular processes contribute to neuronal outgrowth and guidance during development, ageing and disease. Ultimately, the knowledge gained may lead to important changes in how we currently treat patients with different neuronal disorders, and it might thus, for example, contribute to successful treatment approaches to spinal cord injuries.