Cortical synaptogenesis is thought to be initially imprecise and refined over time. We suspect that the final arrangement of CMS synapses is an example of """"""""sorting"""""""" or """"""""reshuffling"""""""" based on specific pre-to- postsynaptic interactions. Via their binding specificity, adhesion molecules are the basis for """"""""sorting"""""""" cells into groups and layers throughout embryonic development and have been thought to function similarly during synaptogenesis as well. Molecules that mediate fine specificity and sorting during synaptogenesis are expected to be differentially expressed in unpredictable combinations in neurons of the same type and from the same lineages. The clustered protocadherins (Pcdhs), novel putative neural adhesion/recognition molecules, exhibit properties expected of molecules that mediate a precise level of synaptic recognition. Their genes are organized into unusual clusters that may reflect the mechanism by which unpredictable combinations of different Pcdhs can be expressed within similar neuronal types. Based on our data and work from others, we hypothesize that the Pcdhs are a basis for a recognition """"""""code"""""""" among neurons by controlling the sorting of intracellular membrane bound synaptic proteins to correctly matched nascent synapses during synaptogenesis resulting in synaptic maturation. We propose two Specific Aims to test our hypothesis.
In Aim 1, we will determine whether Pcdhs are actually adhesion/recognition molecules and characterize their cytoplasmic interactions.
In Aim 2, we will characterize the subcellular trafficking and synaptic insertion processes of the Pcdhs that we suspect underlie Pcdh mediated maturation of correctly matched synapses. Upon completion of these Aims we expect to have a better understanding of the role of cell-cell interactions in synaptogenesis.
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