Regulation of cellular interactions and synapse development in the CNS.

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Brains are networks of interconnected cells. Their functions depend on the selective formation of connections, so that they behave as appropriately configured information processing machines. The process of forming connections, though vital, is not well understood, and we are particularly ignorant of what happens in living networks as they form, make connections and begin to function. As nervous systems develop, nerve cell terminals grow. The growth of these terminals is intimately linked to the formation of connections on them. During normal development, nerve terminal growth is therefore tightly regulated, so as to ensure that normal function can emerge. Conversely, mutations in genes that regulate nerve terminal growth or the formation of connections between them have been linked to mental retardation, cognitive disorders and neurodegeneration. In addition to nerve cells, so-called glia cells also contribute to the make up of the nervous system. Glia cells have in recent years become appreciated for their role in regulating the formation and function of connections that nerve cells form between each other. However, our understanding of how glia cells interact with nerve cells so as to regulate nerve terminal growth and connectivity is particularly patchy. One reason for this is that cell-cell interactions are very dynamic and it has been exceedingly challenging to differentially label and image interacting cells in a developing nervous system. We have a simple model network in the fruitfly fly embryo. Importantly, most developmental processes have been conserved during evolution. It is for this reason and because one can do fly genetics with relative ease, that the fruitfly has been instrumental in driving forward our understanding of nervous system development. We have developed new genetic, microscopy and electrophysiological methods that allow us to study and manipulate particular cells in this system. Using genetics, we can differentially label partner nerve and glia cells (with fluorescent dyes). Using our microscope setup we can image how these cells interact as their terminals grow, form connections with one another and mature. We will determine precisely what happens as connections form - we can study it both morphologically and functionally (as a signaling junction) throughout the period of its development. Through a recent genetic screen we have identified a gene called Anaplastic lymphoma kinase (Alk) as an important regulator of nerve terminal growth. Mutations that alter the activity of this gene have been found to cause cancers in humans and this aspect has been studied. However, other functions of Alk, namely during nervous system development are less well understood. Our preliminary work strongly suggests that Alk is important for regulating the communication between nerve cells and glia and that it may thus regulate nerve terminal growth. We will apply our genetic and imaging methods to test this hypothesis. Having established the consequences of what happens to nervous system development when Alk function is altered, we will investigate underlying mechanisms to understand how these changes occur. The results from this work will help us understand the mechanisms and molecules that are required to form a functioning nervous system.