Loss of Mpdz impairs ependymal cell integrity leading to perinatal‐onset hydrocephalus in mice. Issue 7 (12th May 2017)

• Record Type: Journal Article
• Authors: Feldner, Anja; Adam, M Gordian; Tetzlaff, Fabian; Moll, Iris; Komljenovic, Dorde; Sahm, Felix; Bäuerle, Tobias; Ishikawa, Hiroshi; Schroten, Horst; Korff, Thomas; Hofmann, Ilse; Wolburg, Hartwig; von Deimling, Andreas; Fischer, Andreas
• Is Part Of: EMBO molecular medicine. Volume 9:Issue 7(2017)
• Page Start: 890
• Page End: 905
• Publication Date: 2017-05-12
• Subjects: aqueductal stenosis -- cerebrospinal fluid -- ependymal cells -- hydrocephalus -- tight junction; Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.15252/emmm.201606430
• Languages: English
• ISSNs: 1757-4676

Abstract

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. Synopsis: Loss‐of‐function mutations in the human MPDZ gene lead to congenital hydrocephalus. Here, the generation and examination of mouse models are described that resemble human pathology. Disruption of the murine Mpdz gene causes perinatal‐onset hydrocephalus. Loss of Mpdz impairs expression of the planar cell polarity protein Pals1 in ependymal cells and leads to higher RhoA activity. Loss of Mpdz causes disruption of the ependymal cell layer that lines the ventricular system. Ependymal denudation is associated with astrogliosis and obstruction of the cerebral aqueduct in Mpdz ‐deficient mice. Abstract : Loss‐of‐function mutations in the human MPDZ gene lead to congenital hydrocephalus. Here, the generation and examination of mouse models are described that resemble human pathology.