Support for synapses: the role of cell adhesion molecules in glial morphogenesis

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The central nervous system (CNS) consists of the brain, spinal cord and retina (eye). It controls most functions of the body and mind. Despite the importance of these tissues are made up of only two major cell types: neurons and glia. Most researchers focus on neurons because they are the electrical wires passing signals to perform daily functions. However, glial cells outnumber neurons in the CNS and they support neurons to make sure they are healthy and function properly. To make up the CNS, neurons and glia need to meet during development and make specific partnerships that last a lifetime. Glial cells have special shapes so that they can connect to the neurons. Changes in glial shape can make neurons sick and potentially lead to disease. So it is important to understand how glial cells get their shape in the first place so we can make sure they keep it and support the neurons throughout the lifespan. We don't know how glial cells get their shape and meet their neuronal partners. We also don't know exactly what happens to neurons if glial cells don't make these connections in the first place. I want to explore these really important fundamental questions.In order to really understand how glia get their shapes and support neurons the best way is to watch it happen in a living animal during their development. I am an expert in studying glial cells in the retina of the zebrafish using genetics and microscopy techniques. The retina is a really simple CNS tissue, if compared to the brain. I will use the zebrafish to study this very interesting problem as we can see inside it during early development, its retina has neurons and glia just like humans, and we can follow individual cells using fluorescent proteins. Thus, using microscopy I can watch how neurons and glia behave to meet and make their connections in a living fish. I have found that glia are active and change their shapes very quickly to find and contact specific neurons. We don't know what molecules are controlling the glia to find their neuronal partners. To identify molecules I carried out a genetic screen looking for glial cells with shape defects. This identified the cell adhesion molecules, which are important molecules for cell connections in many different tissues, including the retina and brain. However, we don't know how these particular ones work in the glia to control their shapes during development. To find out why these genes are important and how they help the glia find their partners I will delete them in zebrafish and observe how retina development goes wrong in animals without these genes. To achieve this I will use microscopy to watch glia and neurons in retinas that grow abnormally. Finally, I have shown before that if you don't have any glia in the zebrafish retina then it doesn't function properly. So I will test the vision of fish that still have glia but only their shapes, and connections to neurons, are affected. I will test this by using visual behavioral tests and stimulation with specific light patterns, these are experiments that can easily be done and something myself and other experts will work on together to accomplish.My research programme will tell us how glia find their partner neurons, which cell adhesion molecules are important for glia to get their shapes and how they make sure our CNS function normally. These answers will be very important for understanding how our retinas and brains are built in the first place. If we understand how glia shape is set up then maybe it will be the same molecules to maintain the connections, so this will also be very important for keeping each part of the CNS healthy as we age. Finally, these behaviors and molecules might help with discovering drugs and treatments to change glial shape and make sure they connect to neurons and support them again. This will be very important for patients with neurodegenerative diseases, like Alzheimers, or retina degeneration (major cause of blindness).