Structural and functional analysis of zebrafish visual circuits specified by teneurin-3

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The brain is built through connections that are formed during development. These connections have to be very precise in order to allow the brain to fulfil the functions important for our behaviour. Moreover, they also have to be specific so that nerve cells for particular functions are able to communicate with each other. It is therefore not surprising that one of the major challenges in Neuroscience is to understand the mechanisms that lead to such specificity: How does one cell recognise its appropriate partner and form a connection with it? What happens when these connections are not formed correctly? In recent years, several studies, mostly done in cell culture experiments, have identified a number of molecules localised on the surface of cells that play a role in this cell recognition process. However, this list of proteins is far from complete to fully explain the diversity of connections found in the brain. Moreover, what is urgently needed is a robust system where the formation and function of such connections can be studied in the living organism. Our model described in this proposal, the visual system in zebrafish, fulfils this requirement and is excellently suited for such studies. Different neurons in the visual system are responsible to transmit various aspects of visual information to the brain, for example colour, light intensity, or the direction of a movement. Functionally related neurons connect to each other at specific places in the eye and the brain. In a previous published study, we have found that the deletion of a particular protein at the surface of neurons found in the eye and the brain leads to defects in both, cell connectivity and a specific visual function involving motion. This suggests that 1) this protein is important for the appropriate connectivity between certain neurons and 2) these cells and their connections are responsible for transmitting a specific visual information. However, there are still a lot of unknowns to fully understand this process. For example: In which neurons is the candidate protein present and what is their function? How do these cells form the connections with each other during development? Are all cells containing this protein connected to each other and transmit the same functional property or are they diverse? Do other, related proteins have a similar function? With this project we will address these questions in a clear and defined work plan. Our experiments are based on techniques that we have successfully applied before. In a first step, we will use genetic methods to label all the cells, which are positive for our gene, so that we can analyse how these cells look like and with which other cells they connect. We will then characterise the functional properties of these cells. Our previous data suggests that this visual function has to do with a specific motion of objects that are seen by the eye, but it is possible that we will uncover additional functions as well. We will analyse what happens to nerve connections when we delete the gene. Importantly, we already have generated the genetic tools needed for these experiments in our preliminary work presented in this application. Once we have uncovered the function of these cells containing our protein, we will determine if its presence is needed on both, the information-sending and information-receiving neuron. This will give important insights on the mechanism of action for these proteins. Finally, we will assess if other proteins that are related to our candidate fulfil similar functions in specifying connections and for functionally related neurons. Our work described in this project impacts on the general understanding of building connections in the brain. Such knowledge is important not only for our comprehension on brain development, but also because it can help us to develop strategies for a functional recovery after brain damage through trauma or disease.