| Summary: | Nuclear factor one X (NFIX) is a transcription factor required for normal ependymal development. Constitutive loss of <i>Nfix</i> in mice (<i>Nfix<sup>−/−</sup></i>) is associated with hydrocephalus and sloughing of the dorsal ependyma within the lateral ventricles. Previous studies have implicated NFIX in the transcriptional regulation of genes encoding for factors essential to ependymal development. However, the cellular and molecular mechanisms underpinning hydrocephalus in <i>Nfix<sup>−/−</sup></i> mice are unknown. To investigate the role of NFIX in hydrocephalus, we examined ependymal cells in brains from postnatal <i>Nfix<sup>−/−</sup></i> and control (<i>Nfix<sup>+/+</sup></i>) mice using a combination of confocal and electron microscopy. This revealed that the ependymal cells in <i>Nfix<sup>−/−</sup></i> mice exhibited abnormal cilia structure and disrupted localisation of adhesion proteins. Furthermore, we modelled ependymal cell adhesion using epithelial cell culture and revealed changes in extracellular matrix and adherens junction gene expression following knockdown of <i>NFIX</i>. Finally, the ablation of <i>Nfix</i> from ependymal cells in the adult brain using a conditional approach culminated in enlarged ventricles, sloughing of ependymal cells from the lateral ventricles and abnormal localisation of adhesion proteins, which are phenotypes observed during development. Collectively, these data demonstrate a pivotal role for NFIX in the regulation of cell adhesion within ependymal cells of the lateral ventricles.
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