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Microvillus

Tightjunction

-Adherens junction

Desmosome

Gap junction

Gap junction rm*

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▲ FIGURE 6-5 The principal types of cell junctions that connect the columnar epithelial cells lining the small intestine. (a) Schematic cutaway drawing of Intestinal epithelial cells. The basal surface of the cells rests on a basal lamina, and the apical surface is packed with fingerlike microvilli that project into the intestinal lumen. Tight junctions, lying just under the microvilli, prevent the diffusion of many substances between the intestinal lumen and the blood through the extracellular space ceptors to cytoskeletal filaments and signaling molecules; and the cytoskeletal filaments themselves. Tight junctions also control the flow of solutes between the cells forming an epithelial sheet. Gap junctions permit the rapid diffusion of small, water-soluble molecules between the cytoplasm of adjacent cells. Although present in epithelia, gap junctions are also abundant in nonepithelial tissues and structurally are very different from anchoring junctions and tight junctions; they also bear some resemblance to an important cell-cell junction in plants. For these reasons, we wait to consider gap junctions at the end of Section 6.5.

Of the three types of anchoring junctions present in epithelial cells, two participate in cell-cell adhesion, whereas the third participates in cell-matrix adhesion. Adherens junctions, which connect the lateral membranes of adjacent epithelial cells, are usually located near the apical surface, just below the tight junctions (see Figures 6-1 and 6-5). A circumferential belt of actin and myosin filaments in a complex with the adherens junction functions as a tension cable that can internally brace the cell and thereby control its shape.

between cells. Gap junctions allow the movement of small molecules and ions between the cytosols of adjacent cells. The remaining three types of junctions—adherens junctions, spot desmosomes, and hemidesmosomes—are critical to cell-cell and cell-matrix adhesion and signaling. (b) Electron micrograph of a thin section of intestinal epithelial cells, showing relative locations of the different junctions. [Part (b) C. Jacobson et al., 2001, Journal Cell Biol. 152:435-450.]

Epithelial and some other types of cells, such as smooth muscle, are also bound tightly together by desmosomes, buttonlike points of contact sometimes called spot desmosomes. Hemidesmosomes, found mainly on the basal surface of epithelial cells, anchor an epithelium to components of the underlying extracellular matrix, much like nails holding down a carpet. Bundles of intermediate filaments, running parallel to the cell surface or through the cell, rather than actin filaments, interconnect spot desmosomes and hemidesmosomes, imparting shape and rigidity to the cell.

Desmosomes and hemidesmosomes also transmit shear forces from one region of a cell layer to the epithelium as a whole, providing strength and rigidity to the entire epithelial cell layer. These junctions are especially important in maintaining the integrity of skin epithelia. For instance, mutations that interfere with hemidesmosomal anchoring in the skin can lead to blistering in which the epithelium becomes detached from its matrix foundation and extracellular fluid accumulates at the basolateral surface, forcing the skin to balloon outward.

Ca2+-Dependent Homophilic Cell-Cell Adhesion in Adherens Junctions and Desmosomes Is Mediated by Cadherins

The primary CAMs in adherens junctions and desmosomes belong to the cadherin family. In vertebrates and invertebrates, this protein family of more than 100 members can be grouped into at least six subfamilies. The diversity of cad-herins arises from the presence of multiple cadherin genes and alternative RNA splicing, which generates multiple mRNAs from one gene.

Cadherins are key molecules in cell-cell adhesion and cell signaling, and they play a critical role during tissue differentiation. The "classical" E-, P-, and N-cadherins are the most widely expressed, particularly during early differentiation. Sheets of polarized epithelial cells, such as those that line the small intestine or kidney tubules, contain abundant E-cadherin along their lateral surfaces. Although E-cadherin is concentrated in adherens junctions, it is present throughout the lateral surfaces where it is thought to link adjacent cell membranes. The brain expresses the largest number of different cadherins, presumably owing to the necessity of forming many very specific cell-cell contacts to help establish its complex wiring diagram.

Classical Cadherins The results of experiments with L cells, a line of cultured mouse fibroblasts grown in the laboratory, demonstrated that E-cadherin and P-cadherin preferentially mediate homophilic interactions. L cells express no cadherins and adhere poorly to themselves or to other types of cultured cells. When genes encoding either E-cadherin or P-cadherin were introduced into L cells with the use of techniques described in Chapter 9, the resulting engineered L cells expressed the encoded cadherin. These cadherin-expressing L cells were found to adhere preferentially to cells expressing the same type

▲ FIGURE 6-7 Protein constitutents of typical adherens junctions. The exoplasmic domains of E-cadherin dimers clustered at adherens junctions on adjacent cells (1 and 2) form Ca+2-dependent homophilic interactions. The cytosolic domains of the E-cadherins bind directly or indirectly to multiple adapter proteins that connect the junctions to actin filaments (F-actin) of

Apical surface

Culture dish

Apical surface

Culture dish

Basal Porous Monolayer lamina filter of MDCK cells

Basal Porous Monolayer lamina filter of MDCK cells

▲ EXPERIMENTAL FIGURE 6-6 Madin-Darby canine kidney (MDCK) cells grown in specialized containers provide a useful experimental system for studying epithelial cells.

MDCK cells form a polarized epithelium when grown on a porous membrane filter coated on one side with collagen and other components of the basal lamina. With the use of the special culture dish shown here, the medium on each side of the filter (apical and basal sides of the monolayer) can be experimentally manipulated and the movement of molecules across the layer monitored. Anchoring junctions and tight junctions form only if the growth medium contains sufficient Ca2+.

of cadherin molecules; that is, they mediate homophilic interactions. The L cells expressing E-cadherin also exhibited the polarized distribution of a membrane protein similar to that in epithelial cells, and they formed epithelial-like aggregates with one another and with epithelial cells isolated from lungs.

The adhesiveness of cadherins depends on the presence of extracellular Ca2 + , the property that gave rise to their name (calcium adhering). For example, the adhesion of engineered L cells expressing E-cadherin is prevented when the cells are bathed in a solution (growth medium) that is low in Ca2 + . The role of E-cadherin in adhesion can also be demonstrated the cytoskeleton and participate in intracellular signaling pathways (e.g., p-catenin). Somewhat different sets of adapter proteins are illustrated in the two cells shown to emphasize that a variety of adapters can interact with adherens junctions, which can thereby participate in diverse activities. [Adapted from V. Vasioukhin and E. Fuchs, 2001, Curr. Opin. Cell Biol.13:76.]

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Cytosol

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Vinculin

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