2014 Theses Doctoral

Structural and biophysical characterization of protocadherin extracellular regions

Wolcott, Holly Noelle

Neural circuit assembly requires that the axons and dendrites of the same neuron do not overlap each other while interacting freely with those from different neurons. This requires that each neuron have a unique cell surface identity to that of its neighbors and that neural self-recognition leads to repulsion, a process known as self-avoidance. Self-avoidance is perhaps best understood in Drosophilia, where homophilic recognition between individual Dscam1 isoforms on the cell surface of neurons leads to repulsion between sister dendrites and axons. However, in contrast to Drosophila, where alternative splicing of the Dscam1 gene can generate thousands of isoforms, vertebrate Dscam genes do not generate significant diversity. The most promising candidate to fill this role in vertebrates is the clustered protocadherins (Pcdhs). Despite this hypothesis, little is known about clustered Pcdh proteins and how they interact.
The clustered Pcdh genes are encoded in three contiguous gene loci, Pcdha, Pcdhb, and Pcdhg, which encode three related families of proteins, Pcdhα, -β, and -