Molecular heterogeneity in the choroid plexus epithelium: the 22‐member γ‐protocadherin family is differentially expressed, apically localized, and implicated in CSF regulation

Abstract

The choroid plexus (CP) epithelium develops from the ependyma that lines the ventricular system, and plays a critical role in the development and function of the brain. In addition to being the primary site of CSF production, the CP maintains the blood-CSF barrier via apical tight junctions between epithelial cells. Here we show that the 22-member γ-Protocadherin (γ-Pcdh) family of cell adhesion molecules, which we have implicated previously in synaptogenesis and neuronal survival, is highly expressed by both CP epithelial and ependymal cells, in which γ-Pcdh protein localization is, surprisingly, tightly restricted to the apical membrane. Multi-label immunostaining demonstrates that γ-Pcdhs are excluded from tight junctions, basolateral adherens junctions, and apical cilia tufts. RT-PCR analysis indicates that, as a whole, the CP expresses most members of the Pcdh-γ gene family. Immunostaining using novel monoclonal antibodies specific for single γ-Pcdh proteins shows that individual epithelial cells differ in their apically-localized γ-Pcdh repertoire. Restricted mutation of the Pcdh-γ locus in the choroid plexus and ependyma leads to significant reductions in ventricular volume, without obvious disruptions of epithelial apical-basal polarity. Together, these results suggest an unsuspected role for the γ-Pcdhs in CSF production and demonstrate a surprising molecular heterogeneity in the CP epithelium.

Polarization of membrane associated proteins in the choroid plexus epithelium from normal and slc4a10 knockout mice

“…We here confirm recent reports on the expected expression and basolateral localization of E-cadherin in CPE (Lobas et al, 2012). Nonetheless, E-cadherin is now believed mainly to link to the actin cytoskeleton via the catenins and actinin, rather than the mainly luminal domain spectrins (Nelson, 2008).…”

Development and functions of the choroid plexus–cerebrospinal fluid system

“…This segregation of lineages in the mature ChP may provide a basis for distinct functional domains within the mature hindbrain ChP with regards to CSF production and other functions. Consistent with this model, the regionalization of SHH-expressing cells that is observed in the developing hindbrain ChP may persist in adulthood 53 , and even neighbouring cells differ in their expression of γ-protocadherin, a cell adhesion molecule that is found on the apical surface of ChP epithelium and that might have a role in CSF production 57 . There have been suggestions that ChPs differ in their metabolic rates and adrenergic activity 58, 59 .…”

γ-Protocadherins Interact with Neuroligin-1 and Negatively Regulate Dendritic Spine Morphogenesis

“…Given this, we also sought to co-immunoprecipitate γ-Pcdhs and Nlg1 from lysates prepared from 1 week-old mouse cortex. Using a monoclonal antibody (Lobas et al, 2012) that recognizes the constant domain shared by all γ-Pcdhs and the 4c12 antibody to detect Nlg1, we were able to co-immunoprecipitate Nlg1 with γ-Pcdhs, indicative of an interaction in the brain in vivo (Figure 3B). …”