Our long-term goal is to understand how the molecular constituents of synapses are organized during development, and to determine the mechanisms that regulate them during plasticity. During more than a decade, our studies have centered on the role of Discs-Large, a scaffolding protein of the PSD95 family. These studies have been instrumental to understanding the dynamics of synapse growth, how scaffolding proteins are regulated, and what additional proteins are required for synaptic protein assembly. More recently, our studies have centered on the regulation of the synaptic cytoskeleton during synapse growth. We have found that a conserved cassette, consisting of the scaffolding proteins Bazooka/Par-3, Par6, and aPKC, plays a primary role in cytoskeletal rearrangements required for new synapse formation. In epithelial cells this complex is necessary to establish cell polarity, and alterations in these proteins result in loss of cell polarity and cancer. In the present proposal we will center on the molecular mechanism by which microtubule dynamics are regulated during synapse growth.
In aim 1 we use a genetic analysis in fixed and living preparations to test the hypothesis that aPKC regulates pre- and postsynaptic microtubule dynamics, and that this is required for new synapse formation.
In Aim 2 we will investigate the role of Putsch, a microtubule associated protein regulated by aPKC. Finally, in aim 3 we will investigate the role of Baz in synaptic development. We expect that the proposed studies will substantially contribute to an understanding of the role of the cytoskeleton during new synapse formation. Because many of these proteins are highly conserved across diverse phylogenies, our studies in Drosophila will also be relevant to vertebrates and mammals, as we have demonstrated in our previous work. An understanding of the factors involved in building a functional synapse will be essential to decipher the mechanisms underlying a number of neural disorders, as well as to design strategies to repair damage after stroke, trauma, or disease.
Showing the most recent 10 out of 24 publications
