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The inner CSF-brain barrier: developmentally controlled access to the brain via intercellular junctions.

Whish S, Dziegielewska KM, Møllgård K, Noor NM, Liddelow SA, Habgood MD, Richardson SJ, Saunders NR - Front Neurosci (2015)

Bottom Line: These intercellular connections do not provide a diffusional restrain between the two compartments.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Therapeutics, University of Melbourne Parkville, VIC, Australia.

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.

No MeSH data available.


Related in: MedlinePlus

Tight and adherens junctional proteins in embryonic mouse brain. An overall view of tight and adherens junctional proteins in the ventricular zone of early mouse CSF-brain interface at low magnification in coronal sections of E16 brain showing immunostaining for claudin-5 (A), α-catenin (B), N-cadherin (C), and β –catenin (D). Note the differences in distribution of immunopositive staining between different regions of the surface of the ventricular zone with strongest staining of the dorsolateral telencephalic wall (DLTW) and a weak or lacking immunoreactivity of the ganglionic eminence (GE). Arrows in A point to the border of faint claudin-5 reactivity of the ventricular surface of the dorsolateral wall, and in (C) to the increased staining of the dorsolateral and ventral borders of the ganglionic eminence. The boxed areas in (A–D) are shown in higher magnification in Figure 7. HIP, hippocampus; LV, lateral ventricle; SF, septal fork of the lateral ventricle; SVZ, septal ventricular zone. (A–D) Same magnification, scale bar 500 μm.
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Figure 6: Tight and adherens junctional proteins in embryonic mouse brain. An overall view of tight and adherens junctional proteins in the ventricular zone of early mouse CSF-brain interface at low magnification in coronal sections of E16 brain showing immunostaining for claudin-5 (A), α-catenin (B), N-cadherin (C), and β –catenin (D). Note the differences in distribution of immunopositive staining between different regions of the surface of the ventricular zone with strongest staining of the dorsolateral telencephalic wall (DLTW) and a weak or lacking immunoreactivity of the ganglionic eminence (GE). Arrows in A point to the border of faint claudin-5 reactivity of the ventricular surface of the dorsolateral wall, and in (C) to the increased staining of the dorsolateral and ventral borders of the ganglionic eminence. The boxed areas in (A–D) are shown in higher magnification in Figure 7. HIP, hippocampus; LV, lateral ventricle; SF, septal fork of the lateral ventricle; SVZ, septal ventricular zone. (A–D) Same magnification, scale bar 500 μm.

Mentions: The overall distribution and cellular localization of the adherens junctional proteins N-cadherin (product of gene Cdh2), α- and β-catenin (Ctnna1 and Ctnnb1) and of the tight junctional proteins claudin-5 and -11, (Cldn5 and Cldn11), were investigated using immunohistochemistry in paraffin embedded sections of mouse brains from E15/16 to adult. These protein candidates were chosen based on the transcriptomic analysis of the dataset as described above (see Tables 3–5). N-cadherin (Cdh2) and both catenin genes (Ctnna1 and Ctnnb1) were expressed at levels that were higher in the fetal brains. Cldn5 was only detected in the fetal ventricular zone while Cldn11 was only detected in the adult. Although transcriptomic analysis was performed on samples dissected out from only the lateral wall of the lateral ventricles and most of the permeability data were also calculated from this area, results from immunohistochemical staining are described for all areas lining the ventricles and are illustrated in Figures 6–8.


The inner CSF-brain barrier: developmentally controlled access to the brain via intercellular junctions.

Whish S, Dziegielewska KM, Møllgård K, Noor NM, Liddelow SA, Habgood MD, Richardson SJ, Saunders NR - Front Neurosci (2015)

Tight and adherens junctional proteins in embryonic mouse brain. An overall view of tight and adherens junctional proteins in the ventricular zone of early mouse CSF-brain interface at low magnification in coronal sections of E16 brain showing immunostaining for claudin-5 (A), α-catenin (B), N-cadherin (C), and β –catenin (D). Note the differences in distribution of immunopositive staining between different regions of the surface of the ventricular zone with strongest staining of the dorsolateral telencephalic wall (DLTW) and a weak or lacking immunoreactivity of the ganglionic eminence (GE). Arrows in A point to the border of faint claudin-5 reactivity of the ventricular surface of the dorsolateral wall, and in (C) to the increased staining of the dorsolateral and ventral borders of the ganglionic eminence. The boxed areas in (A–D) are shown in higher magnification in Figure 7. HIP, hippocampus; LV, lateral ventricle; SF, septal fork of the lateral ventricle; SVZ, septal ventricular zone. (A–D) Same magnification, scale bar 500 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 6: Tight and adherens junctional proteins in embryonic mouse brain. An overall view of tight and adherens junctional proteins in the ventricular zone of early mouse CSF-brain interface at low magnification in coronal sections of E16 brain showing immunostaining for claudin-5 (A), α-catenin (B), N-cadherin (C), and β –catenin (D). Note the differences in distribution of immunopositive staining between different regions of the surface of the ventricular zone with strongest staining of the dorsolateral telencephalic wall (DLTW) and a weak or lacking immunoreactivity of the ganglionic eminence (GE). Arrows in A point to the border of faint claudin-5 reactivity of the ventricular surface of the dorsolateral wall, and in (C) to the increased staining of the dorsolateral and ventral borders of the ganglionic eminence. The boxed areas in (A–D) are shown in higher magnification in Figure 7. HIP, hippocampus; LV, lateral ventricle; SF, septal fork of the lateral ventricle; SVZ, septal ventricular zone. (A–D) Same magnification, scale bar 500 μm.
Mentions: The overall distribution and cellular localization of the adherens junctional proteins N-cadherin (product of gene Cdh2), α- and β-catenin (Ctnna1 and Ctnnb1) and of the tight junctional proteins claudin-5 and -11, (Cldn5 and Cldn11), were investigated using immunohistochemistry in paraffin embedded sections of mouse brains from E15/16 to adult. These protein candidates were chosen based on the transcriptomic analysis of the dataset as described above (see Tables 3–5). N-cadherin (Cdh2) and both catenin genes (Ctnna1 and Ctnnb1) were expressed at levels that were higher in the fetal brains. Cldn5 was only detected in the fetal ventricular zone while Cldn11 was only detected in the adult. Although transcriptomic analysis was performed on samples dissected out from only the lateral wall of the lateral ventricles and most of the permeability data were also calculated from this area, results from immunohistochemical staining are described for all areas lining the ventricles and are illustrated in Figures 6–8.

Bottom Line: These intercellular connections do not provide a diffusional restrain between the two compartments.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Therapeutics, University of Melbourne Parkville, VIC, Australia.

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.

No MeSH data available.


Related in: MedlinePlus