Murine MPDZ‐linked hydrocephalus is caused by hyperpermeability of the choroid plexus
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 mediu...
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| Language: | English |
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Springer Nature
2018-12-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201809540 |
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| author | Junning Yang Claire Simonneau Robert Kilker Laura Oakley Matthew D Byrne Zuzana Nichtova Ioana Stefanescu Fnu Pardeep‐Kumar Sushil Tripathi Eric Londin Pascale Saugier‐Veber Belinda Willard Mathew Thakur Stephen Pickup Hiroshi Ishikawa Horst Schroten Richard Smeyne Arie Horowitz |
| author_facet | Junning Yang Claire Simonneau Robert Kilker Laura Oakley Matthew D Byrne Zuzana Nichtova Ioana Stefanescu Fnu Pardeep‐Kumar Sushil Tripathi Eric Londin Pascale Saugier‐Veber Belinda Willard Mathew Thakur Stephen Pickup Hiroshi Ishikawa Horst Schroten Richard Smeyne Arie Horowitz |
| author_sort | Junning Yang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-9e7dfd6574c64708bffe246dee632cbb |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2018-12-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-9e7dfd6574c64708bffe246dee632cbb2025-08-20T03:45:32ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842018-12-0111111910.15252/emmm.201809540Murine MPDZ‐linked hydrocephalus is caused by hyperpermeability of the choroid plexusJunning Yang0Claire Simonneau1Robert Kilker2Laura Oakley3Matthew D Byrne4Zuzana Nichtova5Ioana Stefanescu6Fnu Pardeep‐Kumar7Sushil Tripathi8Eric Londin9Pascale Saugier‐Veber10Belinda Willard11Mathew Thakur12Stephen Pickup13Hiroshi Ishikawa14Horst Schroten15Richard Smeyne16Arie Horowitz17Cardeza Center for Vascular Biology, Sidney Kimmel Medical College, Thomas Jefferson UniversityCardeza Center for Vascular Biology, Sidney Kimmel Medical College, Thomas Jefferson UniversityCardeza Center for Vascular Biology, Sidney Kimmel Medical College, Thomas Jefferson UniversityDepartment of Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson UniversityDepartment of Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson UniversityDepartment of Pathology, Anatomy and Cell Biology, Sidney Kimmel Medical College, Thomas Jefferson UniversityCardeza Center for Vascular Biology, Sidney Kimmel Medical College, Thomas Jefferson UniversityDepartment of Radiology, Sidney Kimmel Medical College, Thomas Jefferson UniversityDepartment of Radiology, Sidney Kimmel Medical College, Thomas Jefferson UniversityComputational Medicine Center, Sidney Kimmel Medical College, Thomas Jefferson UniversityDepartment of Genetics, University of RouenProteomics Core Facility, Lerner Research Institute, Cleveland Clinic FoundationDepartment of Radiology, Sidney Kimmel Medical College, Thomas Jefferson UniversityDepartment of Radiology, University of Pennsylvania Medical SchoolLaboratory of Clinical Regenerative Medicine, Department of Neurosurgery, Faculty of Medicine, University of TsukubaPediatric Infectious Diseases, University Children's Hospital Mannheim, Heidelberg UniversityDepartment of Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson UniversityCardeza Center for Vascular Biology, Sidney Kimmel Medical College, Thomas Jefferson UniversityAbstract 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.https://doi.org/10.15252/emmm.201809540cerebrospinal fluidchoroid plexushydrocephalusmagnetic resonance imagingproteomics |
| spellingShingle | Junning Yang Claire Simonneau Robert Kilker Laura Oakley Matthew D Byrne Zuzana Nichtova Ioana Stefanescu Fnu Pardeep‐Kumar Sushil Tripathi Eric Londin Pascale Saugier‐Veber Belinda Willard Mathew Thakur Stephen Pickup Hiroshi Ishikawa Horst Schroten Richard Smeyne Arie Horowitz Murine MPDZ‐linked hydrocephalus is caused by hyperpermeability of the choroid plexus EMBO Molecular Medicine cerebrospinal fluid choroid plexus hydrocephalus magnetic resonance imaging proteomics |
| title | Murine MPDZ‐linked hydrocephalus is caused by hyperpermeability of the choroid plexus |
| title_full | Murine MPDZ‐linked hydrocephalus is caused by hyperpermeability of the choroid plexus |
| title_fullStr | Murine MPDZ‐linked hydrocephalus is caused by hyperpermeability of the choroid plexus |
| title_full_unstemmed | Murine MPDZ‐linked hydrocephalus is caused by hyperpermeability of the choroid plexus |
| title_short | Murine MPDZ‐linked hydrocephalus is caused by hyperpermeability of the choroid plexus |
| title_sort | murine mpdz linked hydrocephalus is caused by hyperpermeability of the choroid plexus |
| topic | cerebrospinal fluid choroid plexus hydrocephalus magnetic resonance imaging proteomics |
| url | https://doi.org/10.15252/emmm.201809540 |
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