The junctions that don’t fit the scheme: special symmetrical cell-cell junctions of their own kind
- First Online:
- Cite this article as:
- Franke, W.W., Rickelt, S., Barth, M. et al. Cell Tissue Res (2009) 338: 1. doi:10.1007/s00441-009-0849-z
- 882 Downloads
Immunocytochemical, electron-, and immunoelectron-microscopical studies have revealed that, in addition to the four major “textbook categories” of cell-cell junctions (gap junctions, tight junctions, adherens junctions, and desmosomes), a broad range of other junctions exists, such as the tiny puncta adhaerentia minima, the taproot junctions (manubria adhaerentia), the plakophilin-2-containing adherens junctions of mesenchymal or mesenchymally derived cell types including malignantly transformed cells, the composite junctions (areae compositae) of the mature mammalian myocardium, the cortex adhaerens of the eye lens, the interdesmosomal “sandwich” or “stud” junctions in the subapical layers of stratified epithelia and the tumors derived therefrom, and the complexus adhaerentes of the endothelial and virgultar cells of the lymph node sinus. On the basis of their sizes and shapes, other morphological criteria, and their specific molecular ensembles, these junctions and the genes that encode them cannot be subsumed under one of the major categories mentioned above but represent special structures in their own right, appear to serve special functions, and can give rise to specific pathological disorders.
KeywordsJunctions Desmosomes Area composita Filopodium Plaque
junction adhesion molecule
membrane-associated guanylate kinase
mesenchymal stem cells
puncta adhaerentia minima
arrhythmogenic ventricular cardiomyopathies
An essential development in the evolution of multicellular organisms with a variety of tissues serving different functions has obviously been the formation of specific semi-stable and dynamic cell-cell junctions, i.e., architectonically positioned structures of limited size that connect cells of the same or different types into higher order organs. Laterally, i.e., in the same plasma membrane, such assemblies can be homophilic or heterophilic and are generally oriented head-to-head, usually with distinct substructures.
Major junctional types
Gap junctions (nexus) appear as densely packed hemichannels composed of tetraspan membrane proteins, which belong to the connexin family and which are symmetrically oriented into channels that allow cell-cell exchange of small molecules.
Tight junctions (TJ; zonulae or fascial adhaerentes) are arrays of tetraspan transmembrane proteins forming tight-sealing bands of various lengths, often branched or ornamentally woven. These proteins are arranged head-to-head into membrane barrier structures containing cell-type-specific combinations of the claudin and the occludin families of proteins, mostly in association with specific immunoglobulin-like proteins of the junction adhesion molecule (JAM) group spanning the membrane once.
Adherens junctions (AJ) are a group of variously sized and shaped cell-type-specific assemblies of glycoproteins of the cadherin family spanning the membrane once and capable of forming a continuous cell-surrounding belt (zonula adhaerens) or streak-like fascia adhaerens, or local near-isodiametric puncta adhaerentia.
Generally the thickest and most robust junction type is represented by the desmosomes (maculae adhaerentes) formed by special subsets of cadherins (desmogleins, desmocollins).
Molecular components of the major categories (I–IV) and several other forms (1–7) of mammalian symmetrical (homotypic) junctions (JAM junction adhesion molecule, brackets not regularly seen in all cells, nd not decided as yet)
Transmembrane proteins and glycoproteins
Specific plaque proteins (selection of hallmark representatives)
Intermediate-sized filaments (keratins, vimentin, desmin)
Desmogleins Dsg 1–3a
Desmocollins Dsc 1–3a
Reticulum cells of thymus and lymph follicles
II. Adherens junctions
Typical cadherinsa (e.g., E-cadherin, N-cadherin, VE-cadherin, cadherin-11) nectin
α- and β-Catenin, plakoglobin, protein p120, protein ARVCF, protein p0071, neurojunginb, proteins ZO-1-3, afadin, vinculin
Various types of cardiomyocytes
Mesenchymal and neural cells
III. Tight junctions
IV. Gap junctions
All kinds of tissue-forming cells
1. Minimal dot junctions
Puncta adhaerentia minima
α- and β-Catenin, proteins p120, p0071, ARVCF, (plakoglobine), afadin
2. Taproot adherens junctions
Mesenchymal cells in culture
α- and β-Catenin, (plakoglobine), proteins p120, p0071, ARVCF, proteins ZO-1-3, afadin, vinculin
3. Plakophilin-2-containing adherens junctions
Mesenchymally derived cells of high proliferative activity
N-cadherin, cadherin-11 (nectin)
α- and β-Catenin, plakoglobine, proteins p120 and p0071a, plakophilin-2, (plakophilin-3f), proteins ZO-1-3, afadin, vinculin
4. Composite junctions
Cardiomyocytes of maturing and adult heart
Desmoplakin, α- and β-catenin, proteins p120, ARVCF and p0071, plakophilin-2, proteins ZO-1–3
5. Adherens cortex
Eye lens interior
α- and β-Catenin, plakoglobin, protein p120, ezrin, periplakin, periaxin
6. Sandwich junctions
Epidermal stratum spinosum or equivalent layers of other stratified epithelia
7. Complex junctions
Endothelial and virgultar cells of lymph node sinus
Desmoplakin, α- and β-catenin, protein p120, plakoglobin, proteins ZO-1–3, afadin
Gap junctions do not reveal a distinct, i.e., electron microscopically demonstrable cytoplasmic plaque, but their connexins are complexed with cytoplasmic proteins of the membrane-associated guanylate kinase (MAGUK) family, which in turn can interact with microtubules or actin filaments (see anthology by Peracchia 2000).
TJs are also associated with a thin and barely visible coat containing MAGUK proteins, specifically proteins ZO-1 – ZO-3, plus cingulin and a series of other proteins (see anthology by Cereijido and Anderson 2001, notably therein the review by Citi 2001).
AJs are characterized by clearly demonstrable plaque structures of varying thickness, made up of cell-type-specific combinations of armadillo (arm)-type proteins, e.g., plakoglobin, β-catenin, proteins p120, p0071, and ARVCF, and neurojungin, together with vinculin-like or other actin-binding proteins such as α-catenin, vinculin, and afadin (for reviews, see the anthologies of Behrens and Nelson 2004; LaFlamme and Kowalczyk 2008).
The plaques of desmosomes, the cadherins of which can project into (and even through) the mostly prominent and dense plaque, also contain plakoglobin, but in addition plakophilin-2 or combinations of two plakophilins, together with the special plaque protein, desmoplakin (for reviews, see the aforementioned anthologies and Holthöfer et al. 2007; Waschke 2008).
Other junctional types
Puncta adhaerentia minima (minimal dot junctions)
Small junctions of the AJ type, including PAM, have also been frequently observed on long processes and on other surface regions of cells in primary and secondary cultures of mesenchymal cells derived from other tissues such as the interstitial cells of the interior of cardiac valves from various mammalian species, including rat, sheep, cow, and human (e.g., Fig. 1e-g; for details see Barth et al. 2009; and references cited therein). In such interstitial cell cultures, the small AJs are often clustered in specific regions of the filopodia, in particular at their tips, but may also occur on the central cell bodies (Fig. 1e–g). Again, the AJs of such cells, including PAM, have been found to be positive for N-cadherin and cadherin-11, for the arm-proteins β-catenin, plakoglobin, proteins p120, ARVCF, and p0071, and for α-catenin, afadin, and proteins of the ZO-1 group.
Manubria adhaerentia (taproot adherens junction)
That these manubrial cell-cell adhesion systems are indeed true AJ structures is evident from their positive immunostaining reaction for both N-cadherin and cadherin-11, together with a plaque structure positive for α- and β-catenin and proteins p120, p0071, and ARVCF, whereas only weak and variable reactions for plakoglobin have been seen, and MAGUK proteins of the ZO-1—3 group have not yet been identified with any significance (Table 1; see also Wuchter et al. 2007). By contrast, afadin and vinculin have generally been immunoreaction-positive. Moreover, the manubria-filling filopodia typically are intensely reactive for actin and with antibodies to ezrin, moesin, myosin, and α-actinin (for the general α-actinin-richness of the microfilament bundles, including the filopodia, of such cultured MSCs, see also Fig. 7 of Wuchter et al. 2007).
We have found it impressive to follow the fate of these taproot junction structures as the cell-packing density increases with cell culture time. Such studies have demonstrated that the lengths of the cell processes and, correspondingly, of the invaginations dynamically decrease in a spectacular way so that, in cultures of extremely high density, only short residual manubria structures are seen (see, e.g., Fig. 11 of Wuchter et al. 2007). The changes of the molecular packing in these AJ-related manubria junctions during this foreshortening phase will have to be studied in future experiments by using fluorescent-marker-coupled molecules in living cells.
Coniunctiones adhaerentes (plakophilin-2-containing adherens junctions)
Areae compositae (composite junctions)
Recent references reporting that certain mutations in human genes encoding desmosomal proteins and glycoproteins result in arrhythmogenic ventricular cardiomyopathies (ARVC) and references to related topics and reviews
Gerull et al. 2004
Norgett et al. 2000
First animal model (boxer dogs)
Oxford et al. 2007
Antoniades et al. 2006
Rampazzo et al. 2002
Alcalai et al. 2003
Dalal et al. 2006
Norman et al. 2005
Kannankeril et al. 2006
Sen-Chowdhry et al. 2005
Nagaoka et al. 2006
Sen-Chowdhry et al. 2007
Syrris et al. 2006a
Tsatsopoulou et al. 2006
Tsatsopoulou et al. 2006
Yang et al. 2006
Van Tintelen et al. 2006
Lahtinen et al. 2007
Awad et al. 2006
Otterspoor et al. 2007
Pilichou et al. 2006
Fidler et al. 2008
Tsatsopoulou et al. 2006
Joshi-Mukherjee et al. 2008
Ram and Van Wagoner 2008
Syrris et al. 2007
Tandri et al. 2008
Wu et al. 2009
Yu et al. 2008
Qiu et al. 2009 (5 cases)
Garcia-Gras et al. 2006
Heuser et al. 2006
Presentation of a specific plakoglobin test for diagnosis of human ARVC
Asimaki et al. 2009
Asimaki et al. 2007
Syrris et al. 2006b
Beffagna et al. 2007
Cortex adhaerens (adherens cortex)
Iuncturae structae (sandwich junctions)
Whereas the stratum spinosum structures positive for specific TJ markers are often small and inconspicuous, a special heavy metal staining reaction is recognized in some of them, resulting in the appearance of an electron-dense layer between the two plasma membrane domains (Fig. 7; see also, e.g., Figs. 9–11 of Langbein et al. 2002). Depending on the thickness and the extent of this electron-dense middle layer in cell-cell contacts, such structures have been classified as “lamellated junctions” (coniunctiones laminosae) or as iunctura structa (sandwich junctions).
Finally, extremely small, i.e. punctate, TJ-resembling structures have been seen in freeze-fractures preparations and have been tentatively termed puncta occludentia (stud junctions; cf. Schlüter et al. 2007).
The list of “special” junctions summarized in this review is certainly not complete. In particular, we have left out all those AJ-like junctions that couple two apparently highly different cell types, i.e., “heterophilic” or “asymmetric” junctions, simply because the two half-junctions might contain different molecular components from those in “symmetric” junctions. We have also omitted the AJs originally introduced as “contact junctions” (contactus adhaerentes), i.e., highly specialized AJs that have been identified to connect the granular cells of the cerebellar glomeruli. These AJ-type plaque-bearing structures contain N-cadherin and M-cadherin (Rose et al. 1995). Interestingly, however, M-cadherin in these structures obviously does not seem to be essential for life, as abrogation of the gene encoding M-cadherin does not result in major defects but apparently is compensated by an upregulation of N-cadherin (Hollnagel et al. 2002). Thus, irrespective of the molecular organization in the M-cadherin-containing junctions, the special contribution of this glycoprotein to the function of the junction will have to be defined in comparison with N-cadherin.
Therefore, although this review has in general to be considered incomplete, it serves primarily as a mind-opener indicating that further kinds of junctions may well lie just around the corner.
The authors thank Caecilia Kuhn, Christine Grund, and Stefanie Winter-Simanowski for their enthusiastic technical assistance, and Dr. T. Keenan (Virginia Tech. University, Blacksburg, Va., USA) for competent correction and polishing of the text.
This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.