Intestinal epithelial cell polarity defects in disease: lessons from microvillus inclusion disease.

Kerstin Schneeberger,Sabrina Roth,Edward E S Nieuwenhuis,Sabine Middendorp

doi:10.1242/dmm.031088

Abstract

ABSTRACTThe intestinal epithelium is a highly organized tissue. The establishment of epithelial cell polarity, with distinct apical and basolateral plasma membrane domains, is pivotal for both barrier formation and for the uptake and vectorial transport of nutrients. The establishment of cell polarity requires a specialized subcellular machinery to transport and recycle proteins to their appropriate location. In order to understand and treat polarity-associated diseases, it is necessary to understand epithelial cell-specific trafficking mechanisms. In this Review, we focus on cell polarity in the adult mammalian intestine. We discuss how intestinal epithelial polarity is established and maintained, and how disturbances in the trafficking machinery can lead to a polarity-associated disorder, microvillus inclusion disease (MVID). Furthermore, we discuss the recent developments in studying MVID, including the creation of genetically manipulated cell lines, mouse models and intestinal organoids, and their uses in basic and applied research.

Highlights

The intestinal epithelium is a highly organized and rapidly selfrenewing tissue with a proliferative crypt compartment and a differentiated villus compartment
The constant cellular turnover of the intestinal epithelium is maintained by stem cells, which reside at the bottom of the crypt and generate rapidly dividing daughter cells, the transit amplifying (TA) cells
The mislocalization of basolateral proteins correlates with loss of epithelial architecture, cancer development (Fatehullah et al, 2013), and with inflammatory bowel disease (Klunder et al, 2017). In this Review, we focus on the structural regulation of polarity and intracellular transport mechanisms in intestinal epithelial cell (IEC), the importance of which is illustrated by the pathophysiological defects in microvillus inclusion disease (MVID)

Summary

Introduction

The intestinal epithelium is a highly organized and rapidly selfrenewing tissue with a proliferative crypt compartment and a differentiated villus compartment. The establishment of epithelial cell polarity with distinct apical and basolateral plasma membrane domains (described in detail below) is pivotal for barrier formation and for the uptake and vectorial transport (see Glossary, Box 1) of nutrients. The junctional complexes (see Glossary, Box 1) consist of three components – tight junctions, adherens junctions and the desmosomal junctions (Farquhar and Palade, 1963; Giepmans and van Ijzendoorn, 2009; Shen et al, 2011) – whereas the basal part of the basolateral membrane contains hemidesmosomes (Stutzmann et al, 2000) It is not yet clear whether basolateral membranes are affected in MVID, the mislocalization of basolateral proteins, such as transferrin receptor and α2-integrin to the cytoplasm has been reported in some MVID patients and mouse models (Schneeberger et al, 2015; Thoeni et al, 2013). Proteins from both plasma membrane domains can be endocytosed and transported back to their respective membranes via the recycling pathway (Golachowska et al, 2010; Utech et al, 2010) (Fig. 1A)

B Cytoskeletal organization

C MYO5B mutant

C Local induction model

Conclusion