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Molecular mechanisms controlling axonal development and synapse formation

Final Activity Report Summary - SYNAXON (Molecular mechanisms controlling axonal development and synapse formation)

During initial brain wiring, neurons generate more connections than ultimately survive; some of these connections are pruned, whereas others are stabilised to constitute a mature neuronal network. Relatively little is known about the molecular mechanisms that control axonal branch formation and stabilisation. Using frontier technology, we are now able to generate mice lacking a gene of interest in a tissue or cell-type specific-manner to study protein function. We have demonstrated first, that the protein kinase FAK is needed for healthy and dynamic axon establishment, additionally, distribution and amount of the cytoskeleton (the scaffold of the neuron) depends on the presence of FAK protein. Second, we have shown that the extracellular cue, semaphorin 3A is mediating FAK activation to control axonal pruning, an event necessary to adjust the final neuronal network.

Some of the insights of this investigation will probably be applicable for understanding not just the initial development of neural connections but also normal plastic rearrangements of neural connections occurring in the healthy and pathologic brains. Understanding the mechanisms that underlie the formation of neural circuits is not only a major biological challenge, but also has important implications in disease.

For example, there are many common cellular and molecular mechanisms between the processes of pruning by degeneration, as it occurs normally during development, and neuronal degeneration and cell dead in neurodegenerative disorders. Therefore, unravelling the molecular machinery controlling the process of pruning during development is likely to offer new venues to understanding neuropathological states.