Novel roles for y-Protocadherins in the choroid plexus

Abstract

γ-Protocadherins (γ-Pcdhs) are important for neuronal development and regular nervous system patterning. Much of this work is based on the assumption that this family of 22 cadherin-like adhesion molecules acts in the manner of Roger Sperry's hypothesized "molecular code", with homophilic adhesion allowing neurons to find their proper neuronal partners during development. Therefore, most research has focused on the expression and roles of these adhesion molecules in neurons and glia. Although these molecules have been almost exclusively studied in neurons, there is evidence that γ-Pcdhs are also expressed and play important roles in other cells. The work done for this thesis focuses on the roles of γ-Pcdhs in the choroid plexus (CP), a brain epithelial tissue that produces the cerebrospinal fluid, as well as potential roles in neuroimmune interactions. The importance of the CP for proper nervous system development, maintenance, function, and neuro-immunosurveillance has largely been overlooked in the past. Prior to this research, the presence, let alone the function of γ-Pcdhs in the CP was not documented. Here, we show that each epithelial cell of the CP expresses a subset of γ-Pcdhs at high levels, and that restricted disruption of this gene family in the CP and in the adjacent ependymal epithelia of mice results in reduced cerebroventricular volume. Furthermore, we show that CP-restricted mutant mice have altered gene expression in the CP, including groups of genes associated with immune function and with TGFβ signaling pathways, suggesting novel roles for the γ-Pcdhs. Finally, we present preliminary data indicating that expression of the γ-Pcdhs is up-regulated in the CP following an immune challenge (experimental autoimmune encephalomyelitis, a mouse vi model for multiple sclerosis) and that they are expressed in other non-neuronal tissues, which, like the CP, play roles in immunosurveillance. vii TABLE OF CONTENTS LIST OF TABLES………………………………………….……………………..…….ix LIST OF FIGURES………………………………………..…………………………….x