Abstract
In the adult the interface between the cerebrospinal fluid and the brain is lined by the ependymal cells, which are joined by gap junctions. These intercellular connections do not provide a diffusional restrain between the two compartments. However, during development this interface, initially consisting of neuroepithelial cells and later radial glial cells, is characterized by “strap” junctions, which limit the exchange of different sized molecules between cerebrospinal fluid and the brain parenchyma. Here we provide a systematic study of permeability properties of this inner cerebrospinal fluid-brain barrier during mouse development from embryonic day, E17 until adult. Results show that at fetal stages exchange across this barrier is restricted to the smallest molecules (286Da) and the diffusional restraint is progressively removed as the brain develops. By postnatal day P20, molecules the size of plasma proteins (70 kDa) diffuse freely. Transcriptomic analysis of junctional proteins present in the cerebrospinal fluid-brain interface showed expression of adherens junctional proteins, actins, cadherins and catenins changing in a development manner consistent with the observed changes in the permeability studies. Gap junction proteins were only identified in the adult as was claudin-11. Immunohistochemistry was used to localize at the cellular level some of the adherens junctional proteins of genes identified from transcriptomic analysis. N-cadherin, β - and α-catenin immunoreactivity was detected outlining the inner CSF-brain interface from E16; most of these markers were not present in the adult ependyma. Claudin-5 was present in the apical-most part of radial glial cells and in endothelial cells in embryos, but only in endothelial cells including plexus endothelial cells in adults. Claudin-11 was only immunopositive in the adult, consistent with results obtained from transcriptomic analysis. These results provide information about physiological, molecular and morphological-related permeability changes occurring at the inner cerebrospinal fluid-brain barrier during brain development.
Highlights
The exchange of molecules between the brain and the periphery is restricted by specific cellular and biochemical mechanisms present at several interfaces between these two compartments: the blood–brain barrier proper, the blood–cerebrospinal fluid (CSF) barrier, the blood-arachnoid barrier and the CSF–brain barrier only present during brain development (Møllgård et al, 1987; Saunders et al, 2012)
At that age more BDA3 kDa appeared to diffuse into the medial aspect of the ventricle and indicates that the permeability of the inner CSF–brain barrier allows unhindered diffusion of a 3 kDa molecule from about the time of birth in mice (Figures 3, 4)
Molecular characterization, using RNA Sequencing of the ventricular zone and ependyma, identified several genes of known junctional www.frontiersin.org proteins that are expressed at this inner CSF-brain barrier in a developmentally regulated manner
Summary
The exchange of molecules between the brain and the periphery is restricted by specific cellular and biochemical mechanisms present at several interfaces between these two compartments: the blood–brain barrier proper, the blood–cerebrospinal fluid (CSF) barrier, the blood-arachnoid barrier and the (inner) CSF–brain barrier only present during brain development (Møllgård et al, 1987; Saunders et al, 2012). The morphological basis of blood– brain and blood–CSF barriers is the presence of tight junctions between cerebral vascular endothelial cells and choroid plexus epithelial cells respectively. These junctions restrict free diffusion between the blood, the brain parenchyma and the CSF Junctions between cells lining the ventricular system of the developing brain were first described on the basis of conventional electron microscopy as modified tight or intermediate junctions, or as desmosomes (Tennyson and Pappas, 1962; Duckett, 1968; Levitt et al, 1981). Unlike tight junctions, which appear to join cells in a “belt-like fashion” at their luminal lateral cell membranes, these novel junctions, named “strap junctions,” appeared to encircle cells from their ventricular surface (Møllgård et al, 1987) and were shown to www.frontiersin.org
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