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EMBO Mol Med. 2017 Jul;9(7):890-905. doi: 10.15252/emmm.201606430.

Loss of Mpdz impairs ependymal cell integrity leading to perinatal-onset hydrocephalus in mice.

Author information

1
Vascular Signaling and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
2
Division of Medical Physics in Radiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
3
Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.
4
Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
5
Department of NDU Life Sciences, School of Life Dentistry, Nippon Dental University, Chiyoda-ku Tokyo, Japan.
6
Pediatric Infectious Diseases, University Children's Hospital Mannheim Heidelberg University, Mannheim, Germany.
7
Department of Cardiovascular Research, Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany.
8
Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ), Heidelberg, Germany.
9
Vascular Biology, CBTM, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
10
Department of Pathology and Neuropathology, University of Tuebingen, Tuebingen, Germany.
11
Vascular Signaling and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany a.fischer@dkfz.de.
12
Medical Clinic I, Endocrinology and Clinical Chemistry, Heidelberg University Hospital, Heidelberg, Germany.

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.

KEYWORDS:

aqueductal stenosis; cerebrospinal fluid; ependymal cells; hydrocephalus; tight junction

PMID:
28500065
PMCID:
PMC5494508
DOI:
10.15252/emmm.201606430
[Indexed for MEDLINE]
Free PMC Article

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