Disruption of CDH2/N-Cadherin–Based Adherens Junctions Leads to Apoptosis of Ependymal Cells and Denudation of Brain Ventricular Walls

Abstract

Disruption/denudation of the ependymal lining has been associated with the pathogenesis of various human CNS disorders, including hydrocephalus, spina bifida aperta, and periventricular heterotopia. It has been traditionally considered that ependymal denudation is a consequence of mechanical forces such as ventricular enlargement. New evidence indicates that ependymal disruption can precede ventricular dilation, but the cellular and molecular mechanisms involved in the onset of ependymal denudation are unknown. Here, we present a novel model to study ependymal cell pathophysiology and demonstrate that selective disruption of N-cadherin-based adherens junctions is sufficient to provoke progressive ependymal denudation. Blocking N-cadherin function using specific peptides that interfere with the histidine-alanine-valine extracellular homophilic interaction domain caused early pathologic changes characterized by disruption of zonula adherens and abnormal intracellular accumulation of N-cadherin. These changes then triggered massive apoptosis of ependymal cells and denudation of brain ventricular walls. Because no typical extrinsic mechanical factors such as elevated pressure or stretching forces are involved in this model, the critical role of N-cadherin-based adherens junctions in ependymal survival/physiology is highlighted. Furthermore, the results suggest that abnormal adherens junctions between ependymal cells should be considered as key components of the pathogenesis of CNS disorders associated with ependymal denudation.

Expansion of the lateral ventricles and ependymal deficits underlie the hydrocephalus evident in mice lacking the transcription factor NFIX

“…N-cadherin constitutes part of the adherens junction within neuroepithelial/ependymal cells, and is thus postulated to regulate the stability of this cellular layer (Jimenez et al, 2014). With regards to hydrocephalus, disruption of N-cadherin based adherens junctions within an in vitro organotypic model of bovine ventricular ependymal cell development was recently shown to lead to the disruption of ependymal cell adherens junctions, and to culminate in apoptosis of the ependymal cell layer (Oliver et al, 2013). Within this in vitro model there are no extrinsic mechanical factors present, such as elevated ventricular pressure, suggesting that ependymal cell denudation can occur in isolation from increased ventricular pressure, and further implicate N-cadherinmediated adherens junctions as being pivotal for normal ependymal cell biology.…”

“…However, we did not observe any apoptotic cells within the ependymal layer of Nfix mutant mice at either P5 or P10, suggestive of cellular death not playing a direct role in the denudation of the ependyma in these mice. Furthermore, the expression of N-cadherin, a cell-adhesion molecule localised to ependymal cells (Oliver et al, 2013) was not markedly different in Nfix À / À mice at P5 or P10, although the morphology of the ependymal cells expressing this factor was abnormal at P10 (Fig. 13).…”

Neural Stem Cells and Fetal-Onset Hydrocephalus

“…The specific disruption of N-cadherinbased junctions is enough to induce ependymal disruption. Indeed, the use of N-cadherin antibodies or synthetic peptides harboring a cadherin recognition sequence triggers the detachment of ependymal cells from explants of the dorsal wall of the sylvian aqueduct [25]. Further, antibodies against chicken N-cadherin injected into the fetal CSF disrupt the VZ and lead to denudation of the SVZ and formation of periventricular rosettes [26].…”

An update on research priorities in hydrocephalus: overview of the third National Institutes of Health-sponsored symposium “Opportunities for Hydrocephalus Research: Pathways to Better Outcomes”

“…Early pattern formation genes such as SHH, ZIC2, PAX6, and WNT1, neuronal path-finding genes such as L1CAM, genes related to cortical development such as POMT1, and those related to growth regulation such as PIK3CA and AKT3 have been implicated. 1,3,7,10,29,52,53,72,84,85,91,103,122 Developmental disorders presenting with hydrocephalus include neural tube disorders, forebrain and hindbrain developmental disorders, brain growth disorders, and cortical malformations. Alterations in the choroid plexus, ependyma, aqueduct, ventricles, and extraaxial spaces can also lead to hydrocephalus.…”