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Review
. 2010 Feb;2(2):a000125.
doi: 10.1101/cshperspect.a000125.

Intercellular junction assembly, dynamics, and homeostasis

Kathleen J Green  1 , Spiro Getsios, Sergey Troyanovsky, L M Godsel
Affiliations
Review

Intercellular junction assembly, dynamics, and homeostasis

Kathleen J Green et al. Cold Spring Harb Perspect Biol. 2010 Feb.

Abstract

Intercellular anchoring junctions are highly specialized regions of the plasma membrane where members of the cadherin family of transmembrane adhesion molecules on opposing cells interact through their extracellular domains, and through their cytoplasmic domains serve as a platform for organizing cytoskeletal anchors and remodelers. Here we focus on assembly of so-called "anchoring" or "adhering" junctions-adherens junctions (AJs) and desmosomes (DSMs), which associate with actin and intermediate filaments, respectively. We will examine how the assembly and function of AJs and DSMs are intimately connected during embryogenesis and in adult cells and tissues, and in some cases even form specialized "mixed" junctions. We will explore signaling and trafficking machineries that drive assembly and remodeling and how these mechanisms are co-opted in human disease.

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Figures

Figure 1.
Figure 1.
Junction biogenesis in preimplantation mammalian embryos. Following the initial cleavage event of the zygote and throughout the entire 4-cell stage, blastomeres are loosely connected to one another and exhibit a diffuse distribution of E-cadherin. Embryo compaction at the 8-cell stage stabilizes E-cadherin along increasing areas of cell–cell contact and initiates a process of junction assembly, cytoskeletal (actin microfilaments and microtubules) reorganization, and increased polarization of apico-basolateral membrane domains (apical microvilli). Asymmetric cell divisions that give rise to a 16-cell embryo allocate inner daughter cells lacking epithelial characteristics and an outer epithelial cell layer that gradually elaborates actin cytoskeleton-associated adherens and tight junctions (reviewed in Eckert and Fleming 2008). A functional tight junction barrier triggers cavitation and the formation of a fluid-filled blastocoel that contacts the inner cell mass; this process is coordinated with the abrupt assembly of intermediate filament-associated desmosomes in the outer trophectodermal epithelium.
Figure 2.
Figure 2.
Junction biogenesis in vitro and associated cytoskeletal arrangements. Following cell contact in vitro, initial cadherin engagement triggers reorganization of the cytoskeleton, coordinated with downstream assembly of tight junctions and desmosomes. In polarized simple epithelial cells, the maturation of junctional contacts is accompanied by the formation of a circumferential zone of parallel microfilament bundles near the apical region of the cell, below the tight junction barrier. Desmosomes are subjacent to this complex and also appear as disclike structures that extend along the entire lateral border, where they anchor IF to the plasma membrane. MTs also anchor at AJs and DSMs.
Figure 3.
Figure 3.
Ultrastructural relationships between microfilaments, IFs, and associated adhering junctions at keratinocyte cell–cell contacts and during contact formation. (A) Transverse section through cell contact zone between two mouse keratinocytes showing alternating arrangement of AJs and DSMs at the cell margins with their associated actin and IF networks. (B) Cross section of mouse keratinocyte during contact initiation shows the intimate connection between keratin IF bundles, which emanate from the nuclear surface and dive down towards and integrate within actin bundles near the substrate (Reprinted, with permission, from Green et al. 1987).
Figure 4.
Figure 4.
Model depicting possible molecular dynamics of intercellular junction assembly. Molecular players in assembly of the adhesive core (left cell) and junctional plaques (right cell) are depicted, with emphasis on AJs and DSMs assembly. Transmembrane molecules are transported in a MT-dependent fashion toward the plasma membrane, possibly via molecular motors in the kinesin family. Cadherins and nectins (1) initiate the process of assembly of the AJ adhesive interface, whereas initial recruitment of desmocollins (2) is followed by stabilization at sites of junction assembly by desmogleins (3). Cargo loading may be facilitated through armadillo family members in some cases. Junctional plaque assembly occurs through dynamic remodeling of the cortical cytoskeleton, initiated by the cadherin-dependent concentration of actin remodeling proteins at sites of junction assembly to drive actin polymerization and reorganization from branched to bundled actin. In coordination with these changes, desmosomal precursors containing desmoplakin and plakophilin are formed in the cytoplasm in close association with IF. Desmosome precursors (4) subsequently translocate to sites of desmosome assembly in an actomyosin-dependent manner to reinforce the plaque (5), in conjunction with actin rearrangement depending on myosin II (6).
Figure 5.
Figure 5.
Organization of intercellular junctions in the epidermis. Desmosomes and AJs are found throughout the epidermis but AJs enriched in E- and P-cadherin are found in the basal layers whereas the number and surface area occupied by DSMs increases during differentiation, during which time P-cadherin is lost. See Kowalczyk and colleagues (Delva et al. 2009, Fig. 3) for the expression patterns of DSM components during differentiation in epidermis. The TJ barrier is in the granular layer of the epidermis, with structurally definable junctions restricted to the second cell layer.
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