During nervous system development, neurons generate more axonal processes than ultimately survive; some of these axonal branches are pruned, whereas others are stabilized to constitute a mature neuronal network. Relatively little is known about the molecular mechanisms that control axonal branch formation and stabilization. Functional analysis of diverse molecules during development has been carried out by means of the generation of regular mutant mice. However, the early mortality of these mutants has prevented their analysis during postnatal development, particularly in the central nervous system. To overcome this problem, conditional-mutant mice using the Cre/LoxP recombination system has been generated.
Using this technology, the production of mice lacking a gene of interest in a tissue or cell-type specific-manner has been possible. In our previous studies, we have used conditional-mutants to investigate the function of the focal adhesion kinase, FAK. We have demonstrated that FAK is a positive cue for a xonal elongation and a negative cue for axonal branching, and consequently synapse establishment. The aim of this proposal is to characterize the molecular mechanisms by which FAK is controlling axonal development and synapse formation.
Using cell-specific ablation in cortical cultures we propose to accomplish three fundamental goals:
(1) to determine the role of local FAK in axonal elongation and branching in vivo,
(2) to establish the downstream pathways following FAK activation, and
(3) to unravel possible extra-cellular cues that use FAK as an intracellular mediator during axonal development.
I anticipate that some of the insights of this research will increase our understanding not just of the initial development of neural connections but also of normal plastic rearrangements of neural connections occurring in the adult nervous system.
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