Alix-mediated assembly of the actomyosin-tight junction polarity complex preserves epithelial polarity and epithelial barrier.

Yvan Campos,Randall Wakefield,Young-Goo Han,Linda Horner,Elida Gomero,David Solecki,Alessandra D’Azzo,Sharon Frase,Antonella Bongiovanni,Xiaohui Qiu,Wojciech Brutkowski

doi:10.1038/ncomms11876

Abstract

Maintenance of epithelial cell polarity and epithelial barrier relies on the spatial organization of the actin cytoskeleton and proper positioning/assembly of intercellular junctions. However, how these processes are regulated is poorly understood. Here we reveal a key role for the multifunctional protein Alix in both processes. In a knockout mouse model of Alix, we identified overt structural changes in the epithelium of the choroid plexus and in the ependyma, such as asymmetrical cell shape and size, misplacement and abnormal beating of cilia, blebbing of the microvilli. These defects culminate in excessive cell extrusion, enlargement of the lateral ventricles and hydrocephalus. Mechanistically, we find that by interacting with F-actin, the Par complex and ZO-1, Alix ensures the formation and maintenance of the apically restricted actomyosin–tight junction complex. We propose that in this capacity Alix plays a role in the establishment of apical–basal polarity and in the maintenance of the epithelial barrier.

Highlights

Maintenance of epithelial cell polarity and epithelial barrier relies on the spatial organization of the actin cytoskeleton and proper positioning/assembly of intercellular junctions
Cells are aligned in homogeneous layers, connected side by side by tight junctions (TJ) and adherens junctions (AJ), which together make up the apical junctional complex (AJC)
The levels of glial fibrillary acidic protein (GFAP) were high in the ependymal/ sub-ependymal layer of the lateral wall, suggesting that the increased ventricular pressure caused by accumulation of cerebrospinal fluid (CSF) damaged this structure (Supplementary Fig. 1a,b)

Summary

Introduction

Maintenance of epithelial cell polarity and epithelial barrier relies on the spatial organization of the actin cytoskeleton and proper positioning/assembly of intercellular junctions How these processes are regulated is poorly understood. In vitro studies have identified Sphingosine 1-phosphate (S1P) as the signalling molecule produced by the dying cell that activates S1P2 receptors in surrounding neighbouring cells, which in turn, assemble an actomyosin ring around the dying cell[30,31] The latter structure mediates the extrusion of the dying cell from the cell layer, a process that is regulated by the Rho GTPase pathway[31,32]. Despite its high prevalence in the population, the molecular bases of hydrocephalus and the mechanisms regulating CSF homeostasis are still largely unknown

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Conclusion