Complexity and developmental changes in the expression pattern of claudins at the blood–CSF barrier

Abstract

The choroid plexus epithelium controls the movement of solutes between the blood and the cerebrospinal fluid. It has been considered as a functionally more immature interface during brain development than in adult. The anatomical basis of this barrier is the interepithelial choroidal junction whose tightness has been attributed to the presence of claudins. We used quantitative real-time polymerase chain reaction, Western blot and immunohistochemistry to identify different claudins in the choroid plexuses of developing and adult rats. Claudin-1, -2, and -3 were highly and selectively expressed in the choroid plexus as compared to brain or parenchyma microvessels and were localized at epithelial junctions. Claudin-6, -9, -19, and -22 also displayed a previously undescribed choroidal selectivity, while claudin-4, -5, and -16 were enriched in the cerebral microvessels. The choroidal pattern of tight junction protein expression in prenatal brains was already complex and included occludin and zonula occludens proteins. It differed from the adult pattern in that the pore-forming claudin-2, claudin-9, and claudin-22 increased during development, while claudin-3 and claudin-6 decreased. Claudin-2 and claudin-11 presented a mirror image of abundance between lateral ventricle and fourth ventricle choroid plexuses. Imunohistochemical analysis of human fetal and postnatal brains for claudin-1, -2, and -3 demonstrated their early presence and localization at the apico-lateral border of the choroid plexus epithelial cells. Overall, choroidal epithelial tight junctions are already complex in developing brain. The observed differences in claudin expression between developing and adult choroid plexuses may indicate developmental differences in selective blood–cerebrospinal fluid transport functions.Electronic supplementary materialThe online version of this article (doi:10.1007/s00418-012-1001-9) contains supplementary material, which is available to authorized users.

Molecular anatomy and functions of the choroidal blood-cerebrospinal fluid barrier in health and disease

“…Similar data concerning claudin-1, -2, and -3 ontogenic regulation were reported for rat, mouse, and human choroid plexus [74,146]. Importantly, the barrier forming claudin-1 and -3 appear very rapidly after the choroid plexuses start to bulge in the ventricles and differentiate (Fig.…”

“…Claudin-11 was immunodetected at epithelial junctions in mouse choroid plexus [166]. These data need to be confirmed because the antibody used was later found to cross-react with claudin-10 [99], also expressed at the choroid plexus [74]. The peculiar parallel organization of tight junction strands in the choroidal epithelial barrier, initially attributed to claudin-11 [166], could alternatively be related to the choroidal expression of claudin-19, which also forms tight junctions with parallel strands in Schwann cells of the peripheral nervous system [94].…”

“…Indeed, such an approach has already been successfully applied to define new stages of lung maturation in humans. Importantly, claudin proteins are expressed at the junctions linking the epithelial cells in the nascent choroid plexus in human, and evidence of the tightness of these junctions has been provided in embryonic rodents ( [74,80], and see infra). This suggests that the barrier originates as early as the choroid plexus develops.…”

“…The claudin repertoire expressed in a given barrier tissue and the way these proteins dimerize between adjacent cells, confer to this barrier its intrinsic properties in term of permselectivity and impermeability. A thorough analysis of claudin transcripts in rat choroid plexus highlighted three major claudins expressed at high levels, Cldn-1, -2 and -3 [74]. The distribution of these proteins is restricted to the apical tight junctions in the choroidal epithelial cells.…”

“…Besides these three major claudins, a number of other barrier forming and channel forming claudins are expressed in the choroid plexus [74], and some of them, such as claudin-9 and -19 have been immunodetected in apical junctions of the rat choroidal epithelium. Claudin-5, the prototypical BBB claudin, distributes at the junctions in large penetrating stromal vessels in rat and mouse and possibly in some smaller vessels [74,82,146]. Its expression in the choroidal epithelium was not detected in rat and mouse, but was recently described in human neonates [164].…”