Functional analyses of the constant region of CNR/protocadherin-a of the dustered protocadherins

点击翻译按钮获取中文摘要

Clustered protocadherins (Pcdhs) constitute the largest subgroup in the cadherin superfamily. About sixty members of clustered Pcdhs are produced from a unique gene cluster. According to the positions in this gene cluster, clustered protocadherins are further classified into three subfamilies, CNR/protocadherin-alpha (Pcdha), Pcdh-beta and Pcdh-gamma. Since clustered Pcdhs have been reported to localize at synapses and in developing axons, they have been assumed to play important roles in neural circuit formation and/or selective synapse formation. However, the functional roles of clustered Pcdhs have remained to be clarified. In this project, we focused on functions of the constant region, a common cytoplasmic region found in all Pcdha proteins.1. Phenotype analyses of Pcdha mutant miceIntense expression of Pcdha proteins in the olfactory sensory neurons (OSNs) prompted us to examine axonal projection of these neurons to the olfactory glomeruli in Pcdha mutant mice, in which the constant region exons had been deleted by gene targeting. In wild-type mice, OSNs that express a given odorant receptor gene project their axons to one glomerulus in each of the two halves of an olfactory bulb. In the Pcdha mutant mice, however, axonal sorting of OSN axons into glomeruli were perturbed, and multiple, small, extraneous glomeruli for the odorant receptors were observed.2. Roles of the constant region in subcellular localization of Pcdha proteins.Pcdha proteins have two alternative constant regions, A- and B-type. Overexpressed Pcdha proteins with A-type constant region are rarely transported to the plasma membrane. In this project, we examined which domain of the A-type constant region is responsible for the subcellular localization of Pcdha-A type proteins. Our results indicate that a lysine-rich domain near the carboxyl-terminus of A-type constant region interferes transport to the plasma membrane in cell lines and neurons.