Abstract
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.
Highlights
Though congenital hydrocephalus is heritable, it has been linked only to eight genes, one of which is MPDZ
To substantiate the presence of hydrocephalus in the brains of MpdzÀ/À mice, and to distinguish between metabolically active and inert, possibly necrotic tissue, we imaged the brains of Mpdz+/+ and MpdzÀ/À mice by 18Ffluorodeoxyglucose positron emission tomography (PET)
To compare receptor-mediated transcytosis through the CPECs of Mpdz+/+ and MpdzÀ/À mice, we focused on the abundance and endocytosis of the low-density lipoprotein (LDL) receptor, because apolipoprotein E (ApoE), an LDL carrier, was the most over-abundant protein in the cerebrospinal fluid (CSF) of MpdzÀ/À mice
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. 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 Mpdzlinked hydrocephalus
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