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Review
. 2018 Feb 13;11(2):dmm031088.
doi: 10.1242/dmm.031088.

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

Kerstin Schneeberger  1 , Sabrina Roth  1 , Edward E S Nieuwenhuis  1 , Sabine Middendorp  2   3
Affiliations
Review

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

Kerstin Schneeberger et al. Dis Model Mech. .

Abstract

The 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.

Keywords: Epithelial cells; Intestine; Microvillus inclusion disease; Polarity.

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Conflict of interest statement

Competing interestsThe authors declare no competing or financial interests.

Figures

Fig. 1.
Fig. 1.
Schematic overview of the intestinal trafficking machinery. Schematics of polarized mouse enterocytes showing their cell features, cytoskeletal organization and trafficking routes. The apical surface is uppermost. (A) Apically and basolaterally destined proteins follow different pathways (denoted by arrows) to reach their target membrane. The biosynthetic route (route 1) is indicated in black line, the transcytotic route (route 2) in dashed line, and the recycling pathway (route 3) in dotted line. (B) Vesicle transport is mediated by the cytoskeleton. Long-distance transport occurs along microtubules, and is mediated by kinesin and dynein motor proteins. Short-distance transport occurs along actin filaments of the terminal web and is mediated by motor proteins of the myosin family.
Fig. 2.
Fig. 2.
Model to explain MVID pathology caused by mutations in STX3, STXBP2 or MYO5B. The panels depict healthy control and mutant human enterocytes, showing endosomal trafficking routes. The apical surface is uppermost. (A) In healthy (control) enterocytes, vesicles containing apical proteins travel from the Golgi complex to the apical membrane. These vesicles fuse with the apical membrane through the interaction of a v-SNARE with the t-SNARE, syntaxin 3 (STX3) and its binding partner STXBP2. (B) STX3/STXBP2-deficient enterocytes fail to deliver apically destined vesicles to the apical membrane and might instead deliver apical recycling endosomes (AREs) that contain apical proteins to the basolateral membrane, leading to the formation of basolateral microvilli. In the apical membrane, microvilli are distorted or absent and are instead accumulating in microvillus inclusions, which are formed by a yet unresolved mechanism. (C) MYO5B mutant enterocytes also fail to deliver apically destined vesicles to the apical membrane, lack apical microvilli and are prone to form microvillus inclusions. Question marks in B and C indicate unresolved mechanisms.
Fig. 3.
Fig. 3.
Three models to explain the pathological hallmarks of MVID. The panels depict human enterocytes, showing endosomal trafficking routes (black arrows). The apical surface is uppermost. (A) In the trafficking model, defects (depicted by red crosses) in vesicle trafficking (caused by MYO5B mutations, MYO5BMUT) or delivery (caused by STX3 mutations, STX3MUT) result in the subapical accumulation of vesicles and in the lack of appropriately polarized apical proteins. (B) In the recycling model, defects in the recycling and delivery of apical recycling endosomes (AREs) result in the subapical accumulation of apical proteins and in the formation of microvilli-containing macropinosomes. (C) In the local induction model, MVID results in colocalization of ezrin and ezrin kinases in the subapically accumulated AREs to create a signaling platform that results in local ectopic microvillus formation, which leads to the formation of microvillus inclusions (red arrows). In healthy cells, ezrin kinases are transported to the apical membrane where they activate ezrin by phosphorylation to induce microvillus formation.
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