Murine MPDZ‐linked hydrocephalus is caused by hyperpermeability of the choroid plexus
Though congenital hydrocephalus is heritable, it has been linked only to eight genes, one of which is MPDZ . Humans and mice that carry a truncated version of MPDZ incur severe hydrocephalus resulting in acute morbidity and lethality. We show by magnetic resonance imaging that contrast medium penetr...
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| Published in: | EMBO molecular medicine Vol. 11; no. 1; pp. 1 - n/a |
|---|---|
| Main Authors: | , , , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
London
Nature Publishing Group UK
01-01-2019
EMBO Press Wiley Open Access John Wiley and Sons Inc Springer Nature |
| Subjects: | |
| Online Access: | Get full text |
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| Summary: | Though congenital hydrocephalus is heritable, it has been linked only to eight genes, one of which is
MPDZ
. Humans and mice that carry a truncated version of MPDZ incur severe hydrocephalus resulting in acute morbidity and lethality. We show by magnetic resonance imaging that contrast medium penetrates into the brain ventricles of mice carrying a
Mpdz
loss‐of‐function mutation, whereas none is detected in the ventricles of normal mice, implying that the permeability of the choroid plexus epithelial cell monolayer is abnormally high. Comparative proteomic analysis of the cerebrospinal fluid of normal and hydrocephalic mice revealed up to a 53‐fold increase in protein concentration, suggesting that transcytosis through the choroid plexus epithelial cells of
Mpdz
KO mice is substantially higher than in normal mice. These conclusions are supported by ultrastructural evidence, and by immunohistochemistry and cytology data. Our results provide a straightforward and concise explanation for the pathophysiology of
Mpdz
‐linked hydrocephalus.
Synopsis
Dysfunction of the choroid plexus (CP) is a likely cause of hydrocephalus, but the underlying pathophysiological and molecular mechanisms remain unclear. Depletion of Mpdz, a cell junction protein, is shown here to induce paracellular and transcellular hyperpermeability of the CP in mice.
Contrast medium leaks from the choroid plexus into the lateral ventricles of
Mpdz
−/−
mice.
Transmitted electron microscopy (TEM) of the CP of
Mpdz
−/−
mice shows that intercellular junctions between the CP epithelial cells (CPECs) are structurally defective.
The receptor to low‐density lipoprotein is overabundant in CPECs of
Mpdz
−/−
mice by approximately 40%, and its constitutive transcytosis higher by more than 50% compared to CPECs of
Mpdz
+/+
mice.
Fluid‐phase uptake is approximately two‐fold higher than
Mpdz
+/+
mice.
Comparative proteomic analysis of the cerebrospinal fluid of
Mpdz
+/+
and
Mpdz
−/−
mice finds protein overabundance in the latter, including more than 50‐fold abundance of ApoE.
Graphical Abstract
Dysfunction of the choroid plexus (CP) is a likely cause of hydrocephalus, but the underlying pathophysiological and molecular mechanisms remain unclear. Depletion of Mpdz, a cell junction protein, is shown here to induce paracellular and transcellular hyperpermeability of the CP in mice. |
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| Bibliography: | # Correction added online on 10 January 2019 after first online publication: Affiliation 9 was corrected ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 PMCID: PMC6328942 |
| ISSN: | 1757-4676 1757-4684 |
| DOI: | 10.15252/emmm.201809540 |