Journal
JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY
Volume 72, Issue 9, Pages 846-860Publisher
OXFORD UNIV PRESS INC
DOI: 10.1097/NEN.0b013e3182a2d5fe
Keywords
Adherens junctions; Apoptosis; CDH2/N-cadherin; Ependymal cells; Ependymal disruption/denudation; Hydrocephalus; Periventricular heterotopia
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Funding
- Chilean National Commission for Scientific & Technological Research (CONICYT) [Fondecyt 1070241, 1111018, Fondecyt 11100408, Fondecyt 11090373]
- I + D Office at Universidad Austral de Chile (DID-UACh)
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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.
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