A Polarizing Issue: Diversity in the Mechanisms Underlying Apico-Basolateral Polarization In Vivo

Polarization along an apico-basolateral axis is a hallmark of epithelial cells and is essential for their selective barrier and transporter functions, as well as for their ability to provide mechanical resiliency to organs. Loss of polarity along this axis perturbs development and is associated with a wide number of diseases. We describe three steps involved in polarization: symmetry breaking, polarity establishment, and polarity maintenance. While the proteins involved in these processes are highly conserved among epithelial tissues and species, the execution of these steps varies widely and is context dependent. We review both theoretical principles underlying these steps and recent work demonstrating how apico-basolateral polarity is established in vivo in different tissues, highlighting how developmental and physiological contexts play major roles in the execution of the epithelial polarity program.

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Separable mechanisms drive local and global polarity establishment in the C. elegans intestinal epithelium

10.1101/2021.11.01.466827 ◽

2021 ◽

Author(s):

Melissa A Pickett ◽

Maria D. Sallee ◽

Victor F. Naturale ◽

Deniz Akpinaroglu ◽

Joo Lee ◽

...

Keyword(s):

Epithelial Cells ◽

Small Groups ◽

Intestinal Epithelium ◽

Protein Complex ◽

Specific Protein ◽

Dependent Manner ◽

Epithelial Polarity ◽

C Elegans ◽

Polarity Establishment

Apico-basolateral polarization is essential for epithelial cells to function as selective barriers and transporters, and to provide mechanical resiliency to organs. Epithelial polarity is established locally, within individual cells to establish distinct apical, junctional, and basolateral domains, and globally, within a tissue where cells coordinately orient their apico-basolateral axes. Using live imaging of endogenously tagged proteins and tissue specific protein depletion in the C. elegans embryonic intestine, we found that local and global polarity establishment are temporally and genetically separable. Local polarity is initiated prior to global polarity and is robust to perturbation. PAR-3 is required for global polarization across the intestine but is not required for local polarity establishment as small groups of cells are able to correctly establish polarized domains in PAR-3 depleted intestines in an HMR-1/E-cadherin dependent manner. Despite belonging to the same apical protein complex, we additionally find that PAR-3 and PKC-3/aPKC have distinct roles in the establishment and maintenance of local and global polarity. Together, our results indicate that different mechanisms are required for local and global polarity establishment in vivo.

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Patients with Mutations in Gsα Have Reduced Activation of a Downstream Target in Epithelial Tissues due to Haploinsufficiency

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2007-0271 ◽

2007 ◽

Vol 92 (10) ◽

pp. 3941-3948

Author(s):

Stephanie C. Hsu ◽

Joshua D. Groman ◽

Christian A. Merlo ◽

Kathleen Naughton ◽

Pamela L. Zeitlin ◽

...

Keyword(s):

Cystic Fibrosis ◽

Epithelial Cells ◽

G Protein ◽

G Protein Signaling ◽

Protein Signaling ◽

Downstream Target ◽

Epithelial Tissues ◽

Stimulatory G Protein ◽

Normal Controls

Abstract Context: Patients with Albright hereditary osteodystrophy (AHO) have defects in stimulatory G protein signaling due to loss of function mutations in GNAS. The mechanism by which these mutations lead to the AHO phenotype has been difficult to establish due to the inaccessibility of the affected tissues. Objective: The objective of the study was to gain insight into the downstream consequences of abnormal stimulatory G protein signaling in human epithelial tissues. Patients and Design: We assessed transcription of GNAS and Gsα-stimulated activation of the cystic fibrosis transmembrane conductance regulator (CFTR) in AHO patients, compared with normal controls and patients with cystic fibrosis. Main Outcome Measures: Relative expression of Gsα transcripts from each parental GNAS allele and cAMP measurements from nasal epithelial cells were compared among normal controls and AHO patients. In vivo measurements of CFTR function, pulmonary function, and pancreatic function were assessed in AHO patients. Results: GNAS was expressed equally from each allele in normals and two of five AHO patients. cAMP generation was significantly reduced in nasal respiratory epithelial cells from AHO patients, compared with normal controls (0.4 vs. 0.6, P = 0.0008). Activation of CFTR in vivo in nasal (P = 0.0065) and sweat gland epithelia (P = 0.01) of AHO patients was significantly reduced from normal. In three patients, the reduction in activity was comparable with patients with cystic fibrosis due to mutations in CFTR. Yet no AHO patients had pulmonary or pancreatic disease consistent with cystic fibrosis. Conclusions: In humans, haploinsufficiency of GNAS causes a significant reduction in the activation of the downstream target, CFTR, in vivo.

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Epithelial-fibroblastic organization in cultures grown from human embryonic kidney: its significance for morphogenesis in vivo

Journal of Cell Science ◽

10.1242/jcs.39.1.291 ◽

1979 ◽

Vol 39 (1) ◽

pp. 291-298

Author(s):

J.B. Bard

Keyword(s):

Free Surface ◽

Epithelial Cells ◽

Functional Properties ◽

Human Embryonic Kidney ◽

Tissue Differences ◽

Cultured Epithelia ◽

Fibroblastic Cells ◽

Different Tissues

The morphological behaviour of explants of human embryonic kidney has been studied in order to investigate the rules governing interactions between epithelial and fibroblastic cells from the same tissue. When the fragments are cultured, epithelia migrate out first and are followed, a few days later, by cables which grow out from the fragments and which are composed of multilayered fibroblasts. These cables extend through the epithelia to reach the substratum, to which they adhere. The epithelia maintain an upper surface free of spread fibroblasts and are unable to multilayer, although occasional rounded-up cells adhere to this surface. Fibroblasts, however, not only multilayer in the cables but can act as a substratum for epithelial cells which migrate on the cable surface. Fibroblasts and epithelia from kidney thus follow the same behavioural rules that govern the interactions between kidney epithelia and fibroblasts from different tissues. The suggestion that these rules derive from tissue differences and that cells from the same tissue are more tolerant of one another is not borne out. These observations and those reported by others are interpreted in terms of the functional properties of the cells in vivo. It is further pointed out that only those epithelia that maintain a free surface in vivo would be expected to show this property in vitro. Finally, the implications of cells with essentially the same properties generating more than one structure are considered.

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An alternative mode of epithelial polarity in the Drosophila midgut

10.1101/307579 ◽

2018 ◽

Cited By ~ 2

Author(s):

Jia Chen ◽

Aram-Christopher Sayadian ◽

Nick Lowe ◽

Holly E. Lovegrove ◽

Daniel St Johnston

Keyword(s):

Epithelial Cells ◽

Adherens Junctions ◽

Epithelial Polarity ◽

Alternative Mode ◽

Epithelial Tissues ◽

Occluding Junctions ◽

Discs Large ◽

And Function ◽

Adhesion Complex

AbstractApical-basal polarity is essential for the formation and function of epithelial tissues, whereas loss of polarity is a hallmark of tumours. Studies in Drosophila have identified conserved polarity factors that define the apical (Crumbs, Stardust, Par-6, aPKC), junctional (Baz/Par-3) and basolateral (Scribbled, Discs large, Lgl) domains of epithelial cells (1, 2). Because these conserved factors mark equivalent domains in diverse vertebrate and invertebrate epithelial types, it is generally assumed that this system organises polarity in all epithelia. Here we show that this is not the case, as none of these canonical factors are required for the polarisation of the endodermal epithelium of the Drosophila adult midgut. Furthermore, unlike other Drosophila epithelia, the midgut forms occluding junctions above adherens junctions, as in vertebrates, and requires the integrin adhesion complex for polarity (3, 4). Thus, Drosophila contains two types of epithelia that polarise by different mechanisms. Since knock-outs of canonical polarity factors often have little effect on the polarity of vertebrate epithelia, this diversity of polarity mechanisms is likely to be conserved in other animals (5-8).

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Centrosome Aurora A gradient ensures single polarity axis in C. elegans embryos

Biochemical Society Transactions ◽

10.1042/bst20200298 ◽

2020 ◽

Vol 48 (3) ◽

pp. 1243-1253 ◽

Cited By ~ 1

Author(s):

Sukriti Kapoor ◽

Sachin Kotak

Keyword(s):

Symmetry Breaking ◽

Cell Fate ◽

Cell Cortex ◽

Axis Formation ◽

Aurora A Kinase ◽

Aurora A ◽

C Elegans ◽

Cell Embryo ◽

Polarity Establishment

Cellular asymmetries are vital for generating cell fate diversity during development and in stem cells. In the newly fertilized Caenorhabditis elegans embryo, centrosomes are responsible for polarity establishment, i.e. anterior–posterior body axis formation. The signal for polarity originates from the centrosomes and is transmitted to the cell cortex, where it disassembles the actomyosin network. This event leads to symmetry breaking and the establishment of distinct domains of evolutionarily conserved PAR proteins. However, the identity of an essential component that localizes to the centrosomes and promotes symmetry breaking was unknown. Recent work has uncovered that the loss of Aurora A kinase (AIR-1 in C. elegans and hereafter referred to as Aurora A) in the one-cell embryo disrupts stereotypical actomyosin-based cortical flows that occur at the time of polarity establishment. This misregulation of actomyosin flow dynamics results in the occurrence of two polarity axes. Notably, the role of Aurora A in ensuring a single polarity axis is independent of its well-established function in centrosome maturation. The mechanism by which Aurora A directs symmetry breaking is likely through direct regulation of Rho-dependent contractility. In this mini-review, we will discuss the unconventional role of Aurora A kinase in polarity establishment in C. elegans embryos and propose a refined model of centrosome-dependent symmetry breaking.

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A Physiologic Regulator of Collagen-Induced Platelet Aggregation: Inhibition by Clq

Thrombosis and Haemostasis ◽

10.1055/s-0038-1650145 ◽

1981 ◽

Vol 45 (02) ◽

pp. 110-115 ◽

Cited By ~ 5

Author(s):

György Csákó ◽

Eva A Suba

Keyword(s):

Platelet Aggregation ◽

Human Platelet ◽

Platelet Reactivity ◽

High Specificity ◽

Turbidimetric Method ◽

Specific Manner ◽

Aggregation Inhibition ◽

Different Tissues

SummaryPlatelet aggregations were studied by a turbidimetric method in citrated human platelet-rich plasmas (PRP) in vitro. Human Clq inhibited the aggregations caused by collagens derived from different tissues and species. Clq was needed by weight in comparable quantities to collagen for neutralizing the aggregating effect. The dependence of the inhibitory reaction on the preincubation of platelets with Clq and the differences in the occurrence of aggregating substances in supernatants of PRP triggered with collagen in the presence or absence of Clq, confirmed that Clq exerts its effect by preventing fixation of collagen to platelets. In addition, the high specificity of the inhibitory action of Clq for collagen-induced platelet aggregation was demonstrated by results obtained for testing a variety of aggregating agents in combination with Clq and/or collagen.Since normal concentrations of Clq in the blood are in the range of inhibitory doses of Clq for collagen-induced platelet aggregations in vitro and upon activation of complement Clq is known to dissociate from Cl, it is proposed that Clq may participate in a highly specific manner in regulating platelet reactivity to collagen in vivo.

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