CELL JUNCTIONS

PRESENTED BY DR MUSARRAT SHAIKH (P.G. DEPT OF ORAL AND MAXILLOFACIAL PATHOLOGY AND MICROBIOLOGY)

In tissues in which cells are closely packed the cell

membranes of adjoining cells are separated , over most of their extent by a narrow space (about 20 nm). This contact is sufficient to bind cells loosely together , and also allows some degree of movement of individual cells. The cells when come in contact with one another and sometimes with the extra cellular matrix , specialized junctions may form at specific sites on contacting cell membrane

Classification..
Named on the basis whether they are spot like or button shaped MACULA When completely surround the cell like a belt

ZONULA.
Nature of close contact between the cell is also used in the classification

Classified into several different categories as

I. II. UNSPECIALISED CONTACTS SPECIALISED CONTACTS 1. ZONULA OCCLUDENS ( TIGHT JUNCTIONS) 2. ADHESIVE JUNCTIONS a) CELL CELL -- ZONULA ADHERENS ( BELT DESMOSOME ) -- MACULA ADHERENS ( DESMOSOME ) b) CELL TO MATRIX --FOCAL ADHESION --HEMIDESMOSOMES 3. GAP ( COMMUNICATING JUNCTIONS )

Junctions may also occur in certain combinations i.e. junctional complexes eg,. Simple or pseudo stratified epithelium consist of Tight junctions , zonula adherens and desmosome.

UNSPECIALISED CONTACTS
No specialized features on electron microscope examination In the cell membrane are present certain glycoprotein molecules called CELL ADHESION

MOLECULES (CAMs)
At its cytosolic end each CAM is in contact with an intermediate protein.

Fibrous element of the cytoskeleton are attached to these intermediate protein. The other end of CAM juts into the 20 nm intercellular space , and comes in contact with a similar molecule from opposite cell membrane. In this way a path is established from which forces can be transmitted from cytoskeleton of one cell to the other

CAMS and intermediate proteins are of various types. The adhesions of some CAMSs is dependent on the presence of calcium ions , while some others are not dependent on them. Intermediate proteins are also of various types Eg. Catenins , Vinculin , alpha Actinin

SPECIALISED CONTACTS
These junctions can be recognised by electron microscope On the molecular level these junctions typically consist of 3 components

Transmembrane adhesive protein Cytoplasmic adapter protein Cytoskeletal filament

These 3 components differ depending on the type of junction

ZONULA OCCLUDENS (TIGHT JUNCTIONS)

Also known as diffusion barrier. Located at most apical point between adjoining epithelial cells and form a ring or circumferential band , around the cell. The transmembrane proteins are arranged in anastomosing strands encircling the cell The intercellular space is obliterated.

Transmembrane adhesive protein Occludin -- member of claudin family. The cytoplasmic proteins associated with the intercellular portion of transmembrane protein include - cell polarity related proteins - vesicular transport related proteins - tumor suppressor related protein & - transcription factor

FUNCTIONS.. Control the passage of material through intercellular space (eg , from interstitium to lumen of gland ) Define and maintain the apical and basolateral surfaces These junctions can be rapidly formed and disassembled (eg , during leucocyte migration across epithelium & endothelium during wound healing)

SITE. Epithelial cells of salivary glands Epithelia of lung Regions of formidable barrier like blood brain barrier endothelial cells in brain have ZO

Electron micrograph of junctional complex between epithelial cells of a salivary gland tight junctions at boundary of apical and lateral cell membrane

Maximum projection showing zonula occludens (tight) junctions between adjacent epithelial cells in a transverse section of mouse prostate

ADHESIVE JUNCTIONS
They hold cells together or anchor cell to the extracellular matrix Intercellular space is maintained at approximately 20 nm Important in cellular signalling Cytoplasmic components may interact with the cytoskeleton , triggering changes in cell shape or motility. The loss of these contacts may lead to apoptosis in some instances or loss of cell polarity and differentiation or unregulated cell proliferation.

CELL - CELL
ZONULA ADHERENS ( BELT DESMOSOMES )
These junctions extend entirely around the cell , below the occluding junctions.

 Principle transmembrane protein E-cadherins

Cytoplasmic adapter protein catenins

alpha and beta

Cytoskeletal components are Actin filament.

A thin layer of electron dense material is associated with cytoplasmic side of ZA which contain alpha actinin & Vinculin. They anchor actin filaments in this junction. In addition tropomyosin and myosin have also been reported

Electron micrograph of junctional complex between epithelial cells of a salivary gland showing zonula adherens

MACULA ADHERENS (DESMOSOME ) Fr. Gr. Desmo; bond , soma; body

These are localized spot adhesions , located at multiple sites on upper lateral surface of adjoining cells

Site : usually numerous in stratum spinosum layer of epidermis

 Transmembrane protein cadherin family desmoglien , desmocollin 1 & desmocollin 2. Desmoglien located in plasma membrane ; Desmocollin located in intercellular space. These result in a dense line in middle of intercellular space of desmosome Cytoplasmic adapter protein catenin desmoplakin and plakoglobin. They form an electron dense attachment plaque on cytoplasmic side of desmosome. Bundles of prekeratin filaments (10 nm) are associated with this plaque.

Schematic picture of desmosome

Electron micrograph of junctional complex between epithelial cells of a salivary gland showing desmosomes.

Transmission electronmicrograph of an intercellular junction between adjacent cells in the spinous layer of the oral epithelium. The junction is mediated primarily by desmosomes. The desmosomes (D) are arranged in a sawtooth pattern. Bundles of tonofilaments or tonofibrils (TF) extend from the desmosomes into the adjacent cytoplasm. Tonofibrils serve as a cytoskeleton that help to dissipate mechanical stresses placed on the desmosomes and adjacent cell membranes. The bar in the upper part of the figure measures 0.1 micrometer

CELL - MATRIX
FOCAL ADHESIONS
Transmembrane proteins integrin family of CAMs (integrins are heterodimers of different alpha and beta subunits with specificity for various extracellular matrix molecules. Known 8 alpha subunits & 8 beta subunits occur in 24 different combinations)

Cytoplasmic adapter proteins Actin binding proteins alpha actinin , vinculin and tanin. They link transmembrane integrins to actin cytoskeleton

Bonding of integrin to collagen , laminin , fibronectin and other extracellular matrix proteins result in recruitment and remodeling of actin cytoskeleton.

HEMIDESMOSOMES
Its a variant of desmosome found in certain epithelia where abrasion and mechanical shearing forces would tend to separate the epithelium from underlying connective tissue. Found on basal cell surfaces where they provide increased adhesion to basal cell lamina. SITE : typically in cornea & skin. mucosa of oral cavity , esophagus etc..

 Transmembrane adhesive protein Integrins alpha6 and beta4 These bind specifically to basal lamina glycoprotein , laminin and collagen XVII ( BP180 ). Cytoplasmic adapter protein bullous pemphigoid antigen 230 (BP230) & pectin form a dense plaque on cytoplasmic surface of hemidesmosomes The hemidesmosomes link cell to basal lamina , & through additional extracellular molecules , to rest of extracellular matrix.

Schematic diagram showing hemidesmosome

GAP ( COMMUNICATING JUNCTIONS)

These junctions are spot like in shape where intercellular space in this region is reduced to a small gap of 2-3 nm
SITE : Nervous system , Heart & GIT.

 Transmembrane protein of connexin family form aqueous channel between cytoplasm of adjacent cell. 6 connexin molecules form a connexon It has a central channel of approximately 2 nm in diameter The connexon in one cell pair with the connexons in adjacent cell to create patent channel With fluorescent dyes , it has been determined that molecules less than 1200 1500 D can move freely between cells through small pores of these junctions.

Small molecules such as amino acids , sugars , nucleotides and steroids can pass from one cell to another Cyclic AMP can move freely between cells and also apparently increase gap junctions permeability. Intracellular calcium concentration appear to regulate opening and closing of pores in gap junctions Normally intracellular Ca conc. Is less than that of tissue fluid ( hence open junctions). If intracellular Ca rises channels close. In embryo , chemical and electrical signals gap junctions growth and differentiation.

Various junctions in different cells.

Ameloblast : they are joined to each other by terminal bar apparatus (web) , distally at the base of tomes processes. This appearance of a linear structure is produced by alignment of junctional complexes consisting of desmosomes and tight junctions. These junctions are zonular. Junctions at basal end of ameloblast to stratum intermedium are macular Isolated gap junctions present at other levels between ameloblast synchronize activity of cells.

 pic

Odontoblast : the junctions between odontoblast and the ones linking subodontoblastic cells are tight , gap and desmosomes. Some signals that co-ordinate activity of these cells pass through gap junctions.
.

 Cementocyte : cementocytes in cellular cementum have canaliculi. The adjacent canaliculi are often connected and the process within them exhibit gap junctions. Osteoblast : these cells contact one another by means of desmosomes and tight junctions. cell surface adjacent to the bone has many fine cytoplasmic processes , some of which contact underlying osteocytes by tight junctions to form part of transport system throughout bone

Oral mucosa :in stratum spinosum the desmosomes increase in number and are more obvious. The slight shrinkage that appear in most histologic preparations cause cells to separate at all points where desmosomes do not anchor them together. Hence spiny appearance.

Junctional epithelium : the epithelium immediately adjacent to the tooth attach themselves to the tooth by hemidesmosomes within the cell and basal lamina produced by the cell beyond the cell. Like epithelial cells they are joined by desmosomes and gap junction. Tight junctions are rare. Desmosomes are fewer in number , correlated with larger extracellular space.

Fibroblast : fibroblast of periodontal ligament have cilia and many intercellular contacts , a feature that is not particularly common in fibroblast of other fibrous connective tissue. The intercellular contacts are mostly desmosomes and gap junctions. (Intercellular contacts are a feature of fibroblast in fetal-like connective tissue).

Myoepithelial cells : desmosomal attachments with underlying parenchymal cells , gap junctions and hemidesmosomal attachments with basal lamina.

Applied aspect
Cell junctions have important role in differentiation , development and function of normal cells , tissues and organs. The function of these junctions may be altered or disrupted by genetic abnormalities of junctional or cytoskeletal proteins or by autoimmune disease in which circulating antibodies to junctional proteins are present. Eg. Pemphigus vulgaris and pemphigus foliaceous blistering disease of oral mucosa and skin respectively.

Caused by auto antibodies to desmoglien-3 and desmoglien-1 Bullous pemphigoid results from presence of auto antibodies to hemidesmosomal components collagen XVII (BP180) & (BP230) Mutations in two different claudin genes recently have been identified as bases for hereditary hypomagnesaemia and a form of hereditary deafness

Pemphigus : showing separation of epithelial cells from basal cell layer

 Mutations of connexin genes certain kind of deafness , congenital cataract & demyelinating disease Mutations of genes for various desmosomal , hemidesmosomal & intermediate filament proteins several types of epidermolysis bullosa.

References
Antonio Nanci ; Ten cates ORAL HISTOLOGY Development Structure and Function :6th edition

Ross H. et al ; HISTOLOGY : A TEXT BOOK AND ATLAS. 3rd edition Inderbir Singh TEXT BOOK OF HUMAN HISTOLOGY. 3rd edition

 B.K.B. Berkovitz ORAL ANATOMY, EMBRYOLOGY & HISTOLOGY. 3rd edition Richard G. Kessel. BASIC MEDICAL HISTOLOGY.2nd edition.

Thank you