Loss of Mpdz impairs ependymal cell integrity leading to perinatal‐onset hydrocephalus in mice
Abstract Hydrocephalus is a common congenital anomaly. LCAM1 and MPDZ (MUPP1) are the only known human gene loci associated with non‐syndromic hydrocephalus. To investigate functions of the tight junction‐associated protein Mpdz, we generated mouse models. Global Mpdz gene deletion or conditional in...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2017-05-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.201606430 |
| _version_ | 1827059844059758592 |
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| author | Anja Feldner M Gordian Adam Fabian Tetzlaff Iris Moll Dorde Komljenovic Felix Sahm Tobias Bäuerle Hiroshi Ishikawa Horst Schroten Thomas Korff Ilse Hofmann Hartwig Wolburg Andreas von Deimling Andreas Fischer |
| author_facet | Anja Feldner M Gordian Adam Fabian Tetzlaff Iris Moll Dorde Komljenovic Felix Sahm Tobias Bäuerle Hiroshi Ishikawa Horst Schroten Thomas Korff Ilse Hofmann Hartwig Wolburg Andreas von Deimling Andreas Fischer |
| author_sort | Anja Feldner |
| collection | DOAJ |
| description | Abstract Hydrocephalus is a common congenital anomaly. LCAM1 and MPDZ (MUPP1) are the only known human gene loci associated with non‐syndromic hydrocephalus. To investigate functions of the tight junction‐associated protein Mpdz, we generated mouse models. Global Mpdz gene deletion or conditional inactivation in Nestin‐positive cells led to formation of supratentorial hydrocephalus in the early postnatal period. Blood vessels, epithelial cells of the choroid plexus, and cilia on ependymal cells, which line the ventricular system, remained morphologically intact in Mpdz‐deficient brains. However, flow of cerebrospinal fluid through the cerebral aqueduct was blocked from postnatal day 3 onward. Silencing of Mpdz expression in cultured epithelial cells impaired barrier integrity, and loss of Mpdz in astrocytes increased RhoA activity. In Mpdz‐deficient mice, ependymal cells had morphologically normal tight junctions, but expression of the interacting planar cell polarity protein Pals1 was diminished and barrier integrity got progressively lost. Ependymal denudation was accompanied by reactive astrogliosis leading to aqueductal stenosis. This work provides a relevant hydrocephalus mouse model and demonstrates that Mpdz is essential to maintain integrity of the ependyma. |
| first_indexed | 2024-03-07T17:03:08Z |
| format | Article |
| id | doaj.art-a318d3d553d9469faacc85ade9ab0a76 |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2025-02-18T18:47:58Z |
| publishDate | 2017-05-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-a318d3d553d9469faacc85ade9ab0a762024-10-20T11:36:49ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842017-05-019789090510.15252/emmm.201606430Loss of Mpdz impairs ependymal cell integrity leading to perinatal‐onset hydrocephalus in miceAnja Feldner0M Gordian Adam1Fabian Tetzlaff2Iris Moll3Dorde Komljenovic4Felix Sahm5Tobias Bäuerle6Hiroshi Ishikawa7Horst Schroten8Thomas Korff9Ilse Hofmann10Hartwig Wolburg11Andreas von Deimling12Andreas Fischer13Vascular Signaling and Cancer, German Cancer Research Center (DKFZ)Vascular Signaling and Cancer, German Cancer Research Center (DKFZ)Vascular Signaling and Cancer, German Cancer Research Center (DKFZ)Vascular Signaling and Cancer, German Cancer Research Center (DKFZ)Division of Medical Physics in Radiology, German Cancer Research Center (DKFZ)Department of Neuropathology, Institute of Pathology, Ruprecht‐Karls‐University HeidelbergDivision of Medical Physics in Radiology, German Cancer Research Center (DKFZ)Department of NDU Life Sciences, School of Life Dentistry, Nippon Dental University, Chiyoda‐kuPediatric Infectious Diseases, University Children's Hospital Mannheim, Heidelberg UniversityDepartment of Cardiovascular Research, Institute of Physiology and Pathophysiology, Heidelberg UniversityVascular Oncology and Metastasis, German Cancer Research Center (DKFZ)Department of Pathology and Neuropathology, University of TuebingenDepartment of Neuropathology, Institute of Pathology, Ruprecht‐Karls‐University HeidelbergVascular Signaling and Cancer, German Cancer Research Center (DKFZ)Abstract Hydrocephalus is a common congenital anomaly. LCAM1 and MPDZ (MUPP1) are the only known human gene loci associated with non‐syndromic hydrocephalus. To investigate functions of the tight junction‐associated protein Mpdz, we generated mouse models. Global Mpdz gene deletion or conditional inactivation in Nestin‐positive cells led to formation of supratentorial hydrocephalus in the early postnatal period. Blood vessels, epithelial cells of the choroid plexus, and cilia on ependymal cells, which line the ventricular system, remained morphologically intact in Mpdz‐deficient brains. However, flow of cerebrospinal fluid through the cerebral aqueduct was blocked from postnatal day 3 onward. Silencing of Mpdz expression in cultured epithelial cells impaired barrier integrity, and loss of Mpdz in astrocytes increased RhoA activity. In Mpdz‐deficient mice, ependymal cells had morphologically normal tight junctions, but expression of the interacting planar cell polarity protein Pals1 was diminished and barrier integrity got progressively lost. Ependymal denudation was accompanied by reactive astrogliosis leading to aqueductal stenosis. This work provides a relevant hydrocephalus mouse model and demonstrates that Mpdz is essential to maintain integrity of the ependyma.https://doi.org/10.15252/emmm.201606430aqueductal stenosiscerebrospinal fluidependymal cellshydrocephalustight junction |
| spellingShingle | Anja Feldner M Gordian Adam Fabian Tetzlaff Iris Moll Dorde Komljenovic Felix Sahm Tobias Bäuerle Hiroshi Ishikawa Horst Schroten Thomas Korff Ilse Hofmann Hartwig Wolburg Andreas von Deimling Andreas Fischer Loss of Mpdz impairs ependymal cell integrity leading to perinatal‐onset hydrocephalus in mice EMBO Molecular Medicine aqueductal stenosis cerebrospinal fluid ependymal cells hydrocephalus tight junction |
| title | Loss of Mpdz impairs ependymal cell integrity leading to perinatal‐onset hydrocephalus in mice |
| title_full | Loss of Mpdz impairs ependymal cell integrity leading to perinatal‐onset hydrocephalus in mice |
| title_fullStr | Loss of Mpdz impairs ependymal cell integrity leading to perinatal‐onset hydrocephalus in mice |
| title_full_unstemmed | Loss of Mpdz impairs ependymal cell integrity leading to perinatal‐onset hydrocephalus in mice |
| title_short | Loss of Mpdz impairs ependymal cell integrity leading to perinatal‐onset hydrocephalus in mice |
| title_sort | loss of mpdz impairs ependymal cell integrity leading to perinatal onset hydrocephalus in mice |
| topic | aqueductal stenosis cerebrospinal fluid ependymal cells hydrocephalus tight junction |
| url | https://doi.org/10.15252/emmm.201606430 |
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