Inverted apicobasal polarity in health and disease

Abstract

Apicobasal epithelial polarity controls the functional properties of most organs. Thus, there has been extensive research on the molecular intricacies governing the establishment and maintenance of cell polarity. Whereas loss of apicobasal polarity is a well-documented phenomenon associated with multiple diseases, less is known regarding another type of apicobasal polarity alteration - the inversion of polarity. In this Review, we provide a unifying definition of inverted polarity and discuss multiple scenarios in mammalian systems and human health and disease in which apical and basolateral membrane domains are interchanged. This includes mammalian embryo implantation, monogenic diseases and dissemination of cancer cell clusters. For each example, the functional consequences of polarity inversion are assessed, revealing shared outcomes, including modifications in immune surveillance, altered drug sensitivity and changes in adhesions to neighboring cells. Finally, we highlight the molecular alterations associated with inverted apicobasal polarity and provide a molecular framework to connect these changes with the core cell polarity machinery and to explain roles of polarity inversion in health and disease. Based on the current state of the field, failure to respond to extracellular matrix (ECM) cues, increased cellular contractility and membrane trafficking defects are likely to account for most cases of inverted apicobasal polarity.

Keywords: Apicobasal polarity; Embryo implantation; Extracellular matrix sensing; Membrane trafficking; Micropapillary cancer; Monogenic diseases.

Fig. 1.

Hallmarks and consequences of inverted apicobasal polarity in health and disease. (A) Normal epithelial polarity is regulated by the asymmetric localization of mutually antagonistic complexes. The Par and the Crumbs complexes define the apical pole which is enriched in PIP₂, PTEN and ezrin (proteins marked in blue). Below AJs, the Scribble complex defines the basolateral domain, which is enriched in PIP₃ and PI3K (proteins marked in red). ECM sensing through integrins controls the orientation of apicobasal polarity and ensures traction-based collective migration. Basal localization of MHC-II is thought to promote immune clearance of damaged cells by permitting T cell recruitment. Apical localization of the multidrug resistance transporter ABCB1 allows drugs to persist in lumens of epithelia. PIP₃, phosphatidylinositol 3,4,5-phosphate. (B) The pre-implantation blastula displays apical-out polarity, which prevents adhesion to the uterine wall due to apical–apical repulsion. During the menstrual cycle, to permit successful embryo nidation, apical determinants in the endometrium disappear from the lumen-facing membranes while integrins and pinopodes appear. In parallel, polar throphectoderm (TE) cells invert their polarity in response to emergence of the endodermal basal lamina and mural TE cells express integrins at the periphery of the blastula to promote implantation. (C) MVID enterocytes show partial inverted polarity of microvilli structures. MVID with an additional mutation in TTC7A results in fully inverted polarity in these cells. In PKD renal tubules, inverted polarity of ion channels and EGFR contribute to the growth of cysts via altered fluid absorption and secretion. (D) TSIPs arise from micropapillary and mucinous carcinoma. The absence of integrins and presence of mucins at the TSIP periphery prevent cell–ECM interactions resulting in tissue invasion via the collective amoeboid mode of migration. The inverted polarity of ABCB1 enhances cytotoxic drug resistance whereas basolateral localization of MHC-II could limit T cell infiltration and increase immune escape.

Fig. 2.

Molecular pathways controlling apicobasal polarity inversion. Polarizing cue sensing and integration by epithelial cells controls how the apicobasal polarity machinery establish and maintain the appropriate polarity state. The enlarged view of the cell on the right shows how basolateral integrins and growth factor receptors sense ECM adhesive cues and growth factors (orange). Multiple cue-integration pathways (purple) trigger local activation of effectors (green), which control the orientation of the polarity machinery. Integrin engagement activates FAK and Src kinases, which downregulate RhoA activity to reduce actomyosin contractility. Decreased RhoA activity directly promotes the endocytosis and Rab11–Cdc42-dependent transcytosis of apical determinants, such as Pdxl (blue vesicles). Integrin engagement also activates ILK, which repolarizes the microtubule network to favor endocytosis and trafficking of apical determinants. TGFβ signaling via TGFR2 downregulates RhoA activity through phosphorylation of Par6. Impairments in these pathways (pink Xs) cause various degrees of apicobasal polarity inversion. In MVID, mutations in STX3, STXBP2 and Myo5B are thought to cause inverted trafficking of apical cargo towards the basolateral domain. The binding of apical vesicles to STX4, a close homolog of STX3 located basolaterally, could contribute to inverted polarity associated with STX3 mutations. In PKD, PC1 mutations prevent FAK from associating with activated integrins in focal adhesions. Alternatively, mutant PC1 is known to sequester E-cadherin in the cytoplasm, preventing the sensing of polarizing cues from adherens junctions.