5. Epithelial Tissue

lmmotile cilia syndrome

results from a genetic defect that causes an abnormal ciliary beat or the absence of a beat. a. In this syndrome, cilia have axonemes that lack ciliary dynein arms and have other abnormalities. b. The syndrome is associated with recurrent lower respiratory tract infections, reduced fertility in women, and sterility in men.

TEM of tight junction

reveals a narrow region in which the plasma membranes of adjoining cells come in close contact to seal off the intercellular space (Fig. 5.15a). At high resolution, the zonula occludens appears not as a continuous seal but as a series of focal fusions between the cells. These focal fusions are created by transmembrane proteins of adjoining cells that join in the intercellular space (Fig. 5.15b). The arrangement of these proteins in forming the seal is best visualized by the freeze fracture technique (Fig. 5.15c). When the plasma membrane is fractured at the site of the zonula occludens, the junctional proteins are observed on the P-face of the membrane, where they appear as ridge-like structures. The opposing surface of the fractured membrane, the E-face, reveals complementary grooves resulting from detachment of the protein particles from the opposing surface. The ridges and grooves are arranged as a network of anastomosing particle strands, thus creating a functional seal within the intercellular space. The number of strands as well as the degree of anastomosis varies in different cells

Primary cilia containing a 9 + 0 pattern of microtubules function as

signal receptors sensing a flow of fluid in developing organs.

Kartagener's syndrome

which is caused by a structural abnormality that results in absence of dynein arms (Fig. F5.2.1). In addition, EM examination of basal bodies from individuals with Kartagener's syndrome often reveals misoriented basal feet pointing in different directhe tions.

Young's syndrome

which is characterized by malformation of the radial spokes and dynein arms, also affects ciliary function in the respiratory tract.

Several structures are responsible for attachment of the basal lamina to the underlying connective tissue.

• Anchoring fibrils (type VII collagen) are usually found in close association with hemidesmosomes. They either extend from the basal lamina to the structures called anchoring plaques in the connective tissue matrix or loop back to the basal lamina (Fig. 5.34). The anchoring fibrils entrap type III collagen (reticular) fibers in the underlying connective tissue, which ensures sound epithelial anchorage. Anchoring fibrils are critical to the function of the anchoring junctions; mutations in the collagen VII gene result in dystrophic epidermolysis bullosa, an inherited blistering skin disease in which the epithelium is detached below the basement membrane. • Fibrillin microfibrils are 10 to 12 nm in diameter and attach the lamina densa to elastic fibers. Fibrillin microfibrils are known to have elastic properties. A mutation in the fibrillin gene (FBN1) causes Marfan's syndrome and other related connective tissue disorders. • Discrete projections of the lamina densa on its connective tissue side interact directly with the reticular lamina to form an additional binding site with type III collagen.

Cells of exocrine glands exhibit diff erent mechanisms of secretion.

• Merocrine secretion. This secretory product is delivered in membrane-bounded vesicles to the apical surface of the cell. Here vesicles fuse with the plasma membrane and extrude their contents by exocytosis. This is the most common mechanism of secretion and is found, for example, in pancreatic acinar cells. • Apocrine secretion. The secretory product is released in the apical portion of the cell, surrounded by a thin layer of cytoplasm within an envelope of plasma membrane. This mechanism of secretion is found in the lactating mammary gland, where it is responsible for releasing large lipid droplets into the milk. • Holocrine secretion. The secretory product accumulates within the maturing cell, which simultaneously undergoes destruction orchestrated by programmed cell death pathways. Both secretory products and cell debris are discharged into the lumen of the gland. This mechanism is found in sebaceous glands of skin and the tarsal (Meibomian) glands of the eyelid.

Two additional components of the basal domain of the cell membrane,

the anchoring junctions focal adhesions and hemidesmosomes, also participate in the adhesion mechanism between the epithelium and the connective tissue.

cilia are classified as

• Motile cilia have been historically the most studied of all cilia. They are found in large numbers on the apicaldomain of many epithelial cells. Motile cilia and their counterparts, flagella, possess a typical 9 + 2 axonemal organization with microtubule-associated motor proteins that are necessary for the generation of forces needed to induce motility. • Primary cilia (monocilia) are solitary projections found on almost all eukaryotic cells. The term monocilia implies that only a single cilium per cell is usually present. Primary cilia are immotile because of different arrangements of microtubules in the axoneme and lack of microtubule-associated motor proteins. They function as chemosensors, osmosensors, and mechanosensors, and they mediate light sensation, odorant, and sound perception in multiple organs in the body. It is now widely accepted that primary cilia of cells in developing tissues are essential for normal tissue morphogenesis. • Nodal cilia are found in the embryo on the bilaminar embryonic disc at the time of gastrulation. They are concentrated in the area that surrounds the primitive node, hence their name nodal cilia. They have a similar axonemal internal architecture as primary cilia; however, they are distinct in their ability to perform rotational movement. They play an important role in early embryonic development.

There are three types of junctional complexes (Fig. 5.14b):

• Occluding junctions are impermeable and allow epi- thelial cells to function as a barrier. Also called tight junctions, occluding junctions form the primary intercellular diffusion barrier between adjacent cells. • Anchoring junctions provide mechanical stability to epithelial cells by linking the cytoskeleton of one cell to the cytoskeleton of an adjacent cell. These junctions are important in creating and maintaining the structural unity of the epithelium. Anchoring junctions interact with both actin and intermediate filaments and can be found not only on the lateral cell surface but also on the basal domain of the epithelial cell. • Communicating junctions allow direct communication between adjacent cells by diffusion of small (<1,200 Da) molecules

Three major proteins have been identified in the plaque:

• Plectin (450 kDa) functions as a cross-linker of the intermediate filaments that bind them to the hemidesmosome attachment plaque. Recent studies indicate that plectin also interacts with microtubules, actin filaments, and myosin II. Thus, plectin cross-links and integrates all elements of the cytoskeleton. • BP 230 (230 kDa) attaches intermediate filaments to the intercellular attachment plaque. The absence of functional BP 230 causes bullous pemphigoid, a disease characterized clinically by blister formation. High levels of antibodies directed against components of the hemidesmosome, including antibodies against BP 230 and type XVII collagen, are detected in people with this disease. For this reason, BP 230 is called bullous pemphigoid antigen 1(BPAG1), and the collagen XVII molecule is called bullous pemphigoid antigen 2 (BPAG2) or BP 180. • Erbin (180 kDa) mediates the association of BP 230 with integrins.

The ability of epithelia to create a diffusion barrier is controlled by two distinct pathways for transport of substances across the epithelia (Fig. 5.17a):

• The transcellular pathway occurs across the plasma membrane of the epithelial cell. In most of these pathways, transport is active and requires specialized energy-dependent membrane transport proteins and channels. These proteins and channels move selected substances across the apical plasma membrane into the cytoplasm and then across the lateral membrane below the level of the occluding junction into the intercellular compartment. • The paracellular pathway occurs across the zonula occludens between two epithelial cells. The amount of water, electrolytes, and other small molecules transported through this pathway is contingent on the tightness of the zonula occludens. The permeability of an occluding junction depends on the molecular composition of the zonula occludens strands and thus the number of active aqueous channels in the seal (see the following section). Under physiologic conditions, substances trans- ported through this pathway may be regulated or coupled to transcellular transport.

The cells that make up epithelium have three principal characteristics:

• They are closely apposed and adhere to one another by means of specific cell-to-cell adhesion molecules that form specialised cell junctions (Fig. 5.1). • They exhibit functional and morphologic polarity. In other words, different functions are associated with three distinct morphologic surface domains: a free surface or apical domain, a lateral domain, and a basal domain. The properties of each domain are determined by specific lipids and integral membrane proteins. • Their basal surface is attached to an underlying basement membrane, a noncellular, protein- polysaccharide-rich layer demonstrable at the light microscopic level by histochemical methods (see Fig. 1.2, page 6).

In contrast to the desmosome, whose transmembrane proteins belong to the cadherin family of calcium-dependent molecules, the majority of transmembrane proteins found in the hemidesmosome belong to the integrin class of cell matrix receptors. Th ese include

• a4b6 integrin, a heterodimer molecule containing two polypeptide chains. Its extracellular domain enters the basal lamina and interacts with type IV collagen suprastructure containing laminins (laminin-332), entactin/nidogen, or the perlecan. On the extracellular surface of the hemidesmosome, laminin molecules form thread-like anchoring filaments that extend from the integrin molecules to the structure of the basement membrane (Fig. 5.36b). Interaction between laminin-332 and a6b4 integrin stabilizes hemidesmosomes and is essential for hemidesmosome formation and for the maintenance of epithelial adhesion. Mutation of the genes encoding laminin-332 chains results in junctional epidermolysis bullosa, another hereditary blistering skin disease. • type XVII collagen (BPAG2, BP 180), a transmembrane molecule (180 kDa) that regulates expression and function of laminin. In experimental models, type XVII collagen inhibits the migration of endothelial cells during angiogenesis and regulates keratinocyte migration in the skin (see Fig. 5.36b). • CD151 (32 kDa), a glycoprotein that participates in the clustering of integrin receptors to facilitate cell-to-extra- cellular matrix interactions

There are two types ofhemidesmosomes

the classical type (type I) located in the stratum basale of skin, in the lining of the esophagus, in the masticatory and lining mucosae of the oral cavity, as well as in the cells of pseudostratified epithelia of structures such as the trachea, and type II hemidesmosomes are present mostly in the simple columnar epithelia of the intestinal lining. Type I hemidesmosomes are more complex, whereas type II hemidesmosomes have much fewer components.

Lamina Iucida

the electron-lucent component of the basal lamina, is approximately 50 nm wide and is composed of the extracellular regions of the laminin receptors, integrin and dystroglycan molecules of the basal plasma membrane. The proteoglycans, laminin and entactin are also components of the lamina Lucida although they coat the surface of the adjacent lamina densa. Therefore, the integrins and dystroglycans form bonds with the laminin in the lamina lucida, and their intracytoplasmic regions form bonds with components of the cytoskeleton, specifically with talins and a-actinins. In this fashion, the basal plasma membrane becomes affixed to the lamina Lucida.

During early embryonic development, nodal cilia containing a 9 + 0 pattern of microtubules establish

the left-right asymmetry of internal organs. Movement of nodal cilia in the region known as the primitive node generates a leftward or "nodal" flow. Th is flow is detected by sensory receptors on the left side of the body, which then initiate signaling mechanisms that differ from those on the right side of the embryo. When nodal cilia are immotile or absent, nodal flow does not occur, leading to random placement of internal body organs. Therefore, primary ciliary dyskinesia (immotile cilia syndrome) often results in situs inversus, a condition in which the position of the heart and abdominal organs are reversed.

The basal domain of epithelial cells is characterized by several features

•The basement membrane is a specialized structure located next to the basal domain of epithelial cells and the underlying connective tissue stroma. •Cell-to-extracellular matrix junctions anchor the cell to the extracellular matrix; they are represented by focal adhesions and hemidesmosomes. •Basal cell membrane infoldings increase the cell surface area and facilitate morphologic interactions between adjacent cells and extracellular matrix proteins.

alar sheet,

(1 ) A funnel-shaped fibrous membrane, known as the___________ attaches to the microtubules C of the basal body at the transition zone and sweeps upward to merge with the cell membrane at the origin of the cilium. The alar sheet not only ensures a strong attachment of the basal body to the plasmalemma but also functions as a semipermeable membrane that limits access to the ciliary cytoplasm.

basal foot

(2) Attached to the basal body is a structure known as the ________ that is believed to ensure that all cilia of the same cell are facing in the same direction, thereby controlling the synchronous, unidirectional bending of all cilia of the same cell.

striated rootlet,

(3) Extending from the basal body, and securing it into the cytoplasm, are the protofilaments, known as the _______ which affixes the cilium relatively deeply into the apical cytoplasm.

mucous membrane (mucosa)

those cavities that connect with the outside of the body, namely, the alimentary canal, the respiratory tract, and the genitourinary tract. It consists of surface epithelium (with or without glands), a supporting connective tissue called the lamina propria, a basement membrane separating the epithelium from the lamina propria, and sometimes a layer of smooth muscle called the muscularis mucosae as the deepest layer.

Darier disease

(also known as keratosis follicularis) is recognizable due to the pus-filled, dry, dark regions on the skin (although the pus may be absent). It is an inherited, autosomal dominant, noncontagious condition. Histologically, the keratinocytes of the skin (especially those of the stratum spinosum and stratum granulosum) are rounded, and because the desmosomal contacts are com promised, the intercellular connections are weakened and ineffective, leading to acantholysis. The distinguishing characteristics of the disease are a specific scent of the affected skin and the fragility of the fingernails. On average, 1 in 1 00,000 people is afflicted by Darier disease worldwide. The condition appears to be due to a problem of intracellular trafficking of desmoplakin to the lateral cell membrane during desmosomal assembly.

gap junctions

(communicating junctions; nexus) are not part of the junctional complex and are frequent components of certain tissues other than epithelia (e.g., central nervous system, cardiac muscle, and smooth muscle). 1. ____________are small aqueous pores that are inserted into the plasma membranes that couple adjacent cells metabolically and electrically (see Figure 5.3).

desmosome

(maculae adherentes) are small, discrete, disk-shaped adhesive sites. _________ are commonly found at sites other than the junctional complex, where they join epithelial cells to each other. (1 ) __________ are characterized by having five regions, two intracellular regions in each cell, namely the outer dense plaque and inner dense plaque, and an extracellular region, known as the extracellular core, in the space between the two cells. (2) The extracellular moieties of the transmembrane glycoproteins, desmogleins, and desmocollins, members of the E-cadherin superfamily, of one cell contact desmogleins and desmocollins of the other cell in the extracellular space. In order for these glycoproteins to form strong adhesive bonds with their counterparts, Ca2+ ions must be present. These extracellular moieties of desmogleins and desmocollins of each cell form the extracellular core and hold the two cells to each other. (3) The intracellular moieties of desmogleins and desmocollins form bonds with the desmosomal plaque proteins plakoglobins and plakophilins. Additional large proteins, known as desmoplakins, contact both plakoglobins and plakophilins, and together they form the outer dense plaque that presses against the cytoplasmic aspect of each cell membrane. (4) The desmoplakins are large molecules, and their tails extend farther into the cytoplasm where they contact and form bonds with the keratin intermediate filaments of the epithelial cell. This region of bonding between the desmoplakins and the intermediate filaments forms the inner dense plaque, and it is here that the cytoskeleton is affixed to the site of adhesion.

tight junction

(zonula occludens; plural: zonulae occludentes) is a zone that surrounds the entire apical perimeter of adjacent cells and is formed by fusion of the outer leaflets of the cells' plasma membranes (Figure 5.3).

cell adhesion molecules (CAMs)

-proteins found on surface of most cells -aid in binding the cell to the extracellular matrix or to other cells If the binding occurs between different types of CAMs, it is described as heterotypic binding; homotypic binding occurs between CAMs of the same type (Fig. 5.18). CAMs have a selective adhesiveness of relatively low strength, which allows cells to easily join and dissociate.

First-degree burns are lesions caused by heat, friction, or other agents.

1. Damage is limited to the superficial layers of the epithelium (usually the epidermis of the skin). 2. Redness and edema occur, but blisters do not form. a. Mitotically active cells remain viable in the deeper layers of the epidermis. b. They divide and replace the damaged or destroyed cells.

function of basal lamina

1. Structural attachment 2. Compartmentalization 3. Filtration 4. Tissue scaffolding. (The basal laminae also allow cells to migrate under physiologic conditions but act as barriers against tumor cell invasion.) 5. Regulation and signaling. (For instance, the basal lamina of endothelial cells has recently been found to be involved in the regulation of tumor angiogenesis.)

function of epithelial tissue

1. Transcellular transport of molecules from one epithelial surface to another occurs by various processes, including the following: a. Diffusion of oxygen and carbon dioxide across the epithelial cells of lung alveoli and capillaries b. Carrier protein-mediated transport of amino acids and glucose across intestinal epithelia c. Vesicle-mediated transport of immunoglobulin A (IgA) and other molecules 2. Absorption occurs via endocytosis or pinocytosis (see Chapter 3 III A) in various organs (e.g., the proximal convoluted tubule of the kidney; see Chapter 18 II). 3. Secretion of various molecules (e.g., hormones, mucinogen, proteins) occurs by exocytosis. 4. Selective permeability results from the presence of tight junctions between epithelial cells and permits fluids with different compositions and concentrations to exist on separate sides of an epithelial layer (e.g., intestinal epithelium). 5. Protection from abrasion and injury is provided by the epidermis, the epithelial layer of the skin.

Gap junctions are formed by

12 subunits of the connexin protein family. tightly packed channels, each formed by two half- channels called connexons embedded in the facing membranes. These channels are represented by pairs of connexons that bridge the extracellular space between adjacent cells. Each connexon contains six symmetrical subunits of an integral membrane protein called connexin (Cx) that is paired with a similar structure from the adjacent membrane. Therefore, the entire channel consists of 12 subunits. The subunits are confi gured in a circular arrangement to surround a 10-nm-long cylindrical transmembrane channel with a diameter of 2.8 nm

Structure of glands

A gland consists of a functional portion (parenchyma) of secretory and ductal epithelial cells, which is separated by a basal lamina from supporting connective tissue elements (stroma).

The zonula occludens establishes functional domains in the plasma membrane.

As a junction, the zonula occludens controls not only the passage of substances across the epithelial layer but also the movement of lipid rafts containing specific proteins within the plasma membrane itself. The cell is able to segregate certain internal membrane proteins on the apical (free) surface and restrict others to the lateral or basal surfaces. In the intestine, for instance, the enzymes for terminal digestion of peptides and saccharides (dipeptidases and disaccharidases) are localized in the membrane of the microvilli of the apical surface. The Na/K-ATPase that drives salt and transcellular water transport, as well as amino acid and sugar transport, is restricted to the lateral plasma membrane below the zonula occludens.

collagens in basal lamina

At least three types of collagen species are present in the basal lamina; they represent a fraction of the approximately 28 types of collagen found in the body. The major component, comprising 50% of all basal lamina proteins, is type IV collagen. The presence of different type IV collagen isoforms provides specificity to the basal lamina associated with different tissues. Two nonfibrillar types of collagens, type XV collagen and type XVIII collagen, are also found in the basal lamina. Type XV collagen plays an important role in stabilizing the structure of the external lamina in skeletal and cardiac muscle cells, whereas type XVIII collagen is mainly present in vascular and epithelial basal laminae and is believed to function in angiogenesis. In addition, type VII collagen forms anchoring fibrils that link the basal lamina to the underlying reticular lamina (described below)

how cilia and flagella move

Ciliary movement occurs as the dynein arms of a doublet grasp and "climb" along the "back" of the adjacent doublet, thereby bending the cilia in a preferred direction. This is an energy-requiring process and is fueled by the ATPase activity of the dynein arms. As the cilium bends, the elastic proteins of the axoneme become stretched. Once the cilium is bent sufficiently, the dynein arms relax their grasp on the adjacent doublet, and the cilium snaps back to its original position propelling materials located at its tip, thus moving material, such as mucus in the tracheal lumen, along the epithelial surface. The process of "snapping back" does not require energy because it is fueled by the stretched elastic proteins returning to their resting positions

Compound tubular

Duodenum: submucosal glands of Brunner Compound tubular glands with coiled secretory portions are located deep in the submucosa of the duodenum

Classification

Epithelia are classified into various types based on the number of cell layers (one cell layer is simple; more than one is stratified) and the shape of the superficial cells (Figure 5.1). Therefore, all cells composing a simple epithelium contact the basal lamina, whereas in stratified epithelia only the deepest cell layer contacts the basal lamina. Pseudostratified epithelia give the appearance of having multiple cell layers, but they are composed of a single cell layer only, as evidenced by the fact that all cells that compose this type of epithelium are in contact with the basal lamina (Figure 5.2).

Structure of epithelial tissue

Epithelia are specialized layers of tissue arising from all three embryonic germ layers, namely, the ectoderm, mesoderm, and endoderm, that line the internal and cover the external surfaces of the body except in certain areas such as tooth surfaces and articular cartilages. An epithelium consists of a sheet of cells lying close together with little extracellular space. These cells have distinct biochemical, functional, and structural domains that confer polarity, or sidedness; thus, these cells are said to have apical, lateral, and basal epithelial domains (or as some authors prefer: basolateral domain). 1. A basement membrane, composed of a basal lamina and a lamina reticularis, separates the epithelium from underlying connective tissue and blood vessels. 2. Epithelia are avascular and receive nourishment by diffusion of molecules through the basal lamina to which they are attached.

metaplasia

Epithelia sometimes undergo metaplasia in response to persistent injury. M eta plasia is the conversion of one type of differentiated epithe lium into another. Most commonly, a glandular e pithelium is transformed into a squamous epithelium. However, in cases of chronic acid reflux from the stomach into the lower esopha gus, the stratified squamous non keratinized epithelium is replaced by a glandular mucus secreting epithelium (Barrett epithelium) similar to that found lining the cardia of the stomach. This helps to protect the esophagus against the injurious effects of the acid and pepsin, but is also a well-known precursor of esophageal adenocarcinoma.

Mutations in connexin genes are major pathogenic factors in several diseases.

For instance, a mutation in the gene encoding connexin-26 (Cx26) is associated with congenital deafness. The gap junctions formed by Cx26 are found in the inner ear and are responsible for recirculating K in the cochlear sensory epithelium. Other mutations affecting Cx46 and Cx50 genes have been identified in patients with inherited cataracts. Both proteins are localized within the lens of the eye and form extensive gap junctions between the epithelial cells and lens fibers. These gap junctions play a crucial role in delivering nutrients to and removing metabolites from the avascular environment of the lens.

Classification of glands

Glands are classified into three types based on the site of secretion. Exocrine glands secrete into a duct or onto a surface. Endocrine glands secrete into the bloodstream. Paracrine glands secrete into the local extracellular space.

The cells of different epithelia require different types of attachments.

In epithelia that serve as physiologic barriers, the junctional complex is particularly significant because it serves to create a long-term barrier, allowing the cells to compartmentalize and restrict the free passage of substances across the epithelium. Although it is the zonula occludens of the junctional complex that principally affects this function, it is the adhesive properties of the zonulae and maculae adherentes that guard against physical disruption of the barrier. In other epithelia, there is a need for substantially stronger attachment between cells in several planes. In the stratified epithelial cells of the epidermis, for example, numerous maculae adherentes maintain adhesion between adjacent cells. In cardiac muscle, where there is a similar need for strong adhesion, a combination of the macula adherens and the fascia adherens serves this function.

intraflagellar transport (IFT)

Kinesin and dynein transport materials into and out of both growing and mature structures promoting growth and maintenance, as well as cilia mediate cell-cell signaling the IFT utilizes raft-like platforms assembled from about 17 different intraflagellar transport proteins that move up and down the growing axoneme between the outer doublets of microtubules and plasma membrane of the elongating cilium. Utilizing kinesin II as a motor protein, the fully loaded platform is moved up- ward toward the tip of the cilium (anterograde transport). Several proteins, including IFT raft proteins (kinesis, cytoplasmic dynein, polaris, IFT20, etc.), are important to ciliogenesis and subsequent maintenance of the functional cilium. Mutations in genes encoding these proteins result in loss of cilia or ciliary dysfunctions.

Simple tubular

Large intestine: intestinal glands of the colon Secretory portion of the gland is a straight tube formed by the secretory cells (goblet cells)

Immunoglobulin superfamily (IgSF).

Many molecules involved in immune reactions share a common precursor element in their structure. However, several other molecules with no known immunologic function also share this same repeat element. Together, the genes encoding these related molecules have been defined as the immunoglobulin gene superfamily. It is one of the largest gene families in the human genome, and its glycoproteins perform a wide variety of important biologic functions. IgSF members mediate homotypic cell-to-cell adhesions and are represented by the intercellular cell adhesion molecule (ICAM), cell-cell adhesion molecule (C-CAM), vascular cell adhesion molecule (VCAM), Down syndrome cell adhesion molecule (DSCAM), platelet endothelial cell adhesion molecules (PECAM), junctional adhesion molecules (JAM), and many others. These proteins play key roles in cell adhesion and differentiation, cancer and tumor metastasis, angiogenesis (new vessel formation), inflammation, immune responses, and microbial attachment, as well as many other functions.

Proteoglycans in basal lamina

Most of the volume of the basal lamina is probably attributable to its proteoglycan content. Proteoglycans consist of a protein core to which heparan sulfate (e.g., perlecan, agrin), chondroitin sulfate (e.g., bamacan), or dermatan sulfate side chains are attached. Because of their highly anionic character, these molecules are extensively hydrated. They also carry a high negative charge; this quality suggests that proteoglycans play a role in regulating the passage of ions across the basal lamina. The most common heparan sulfate proteoglycan found in all basal laminae is the large multidomain proteoglycan perlecan (400 kDa). It provides additional cross-links to the basal lamina by binding to laminin, type IV collagen, and entactin/ nidogen. Agrin (500 kDa) is another important molecule found almost exclusively in the glomerular basement membrane of the kidney. It plays a major role in renal fi ltration as well as in cell-to- extracellular matrix interactions.

Cilia beat in a synchronous pattern.

Motile cilia with a 9 + 2 pattern display a precise and synchronous undulating movement. Cilia in successive rows start their beat so that each row is slightly more advanced in its cycle than the following row, thus creating a wave that sweeps across the epithelium. As previously discussed, basal feet of basal bodies are most likely responsible for the synchronization of ciliary movement. During the process of cilia formation, all basal feet become oriented in the same direction of effective stroke by rotating basal bodies. This orientation allows cilia to achieve a metachronal rhythm that is responsible for moving mucus over epithelial surfaces or facilitating the flow of fluid and other substances through tubular organs and ducts.

Deafness

Mutations of certain connexins genes, which are abundant in the cochlea, are responsible for deafness

Compound acinar

Pancreas: exocrine portion Compound acinar glands with alveolar- shaped secretory units are formed by pyramid-shaped serous-secreting cells

One cell layer

Simple squamous Endothelium (lining of blood vessels). mesothelium (lining of peritoneum and pleura) Simple cuboidal The lining of distal tubule in kidney and ducts in some glands, surface of the ovary Simple columnar The lining of the intestine, stomach, and excretory ducts in some glands Pseudostratified The lining of the trachea, primary bronchi, nasal cavity, and excretory ducts in parotid gland

Simple coiled tubular

Skin: eccrine sweat gland Coiled tubular structure is composed of the secretory portion located deep in the dermis

Branched acinar

Stomach: mucus-secreting glands of cardia Skin: sebaceous glands Branched acinar glands with secretory portions are formed by mucus- secreting cells; the short, single-duct portion opens directly into the lumen

Simple branched tubular

Stomach: mucus-secreting glands of the pylorus Uterus: endometrial glands Branched tubular glands with wide secretory portion are formed by the secretory cells and produce a viscous mucous secretion

More than one cell layer

Stratified squamous (not keratinized) Lining of esophagus, vagina, mouth, and true vocal cords Stratified squamous (keratinized) Epidermis of skin Stratified cuboidal Lining of ducts in sweat glands Stratified columnar Lining of large excretory ducts in some glands and cavernous urethra Transitional Lining of urinary passages from renal calyces to the urethra

Compound tubuloacinar

Submandibular salivary gland Compound tubuloacinar glands can have both mucous branched tubular and serous branched acinar secretory units; they have serous end-caps (demilunes)

zonula adherens

The adhering junction, ___________, surrounds the entire perimeter of the epithelial cell and is located just basal to and reinforcing the zonula occludens (Figure 5.3). (1 ) It is characterized by a 10-to 20-nm separation between the adjoining cell membranes where the extracellular portions of the transmembrane glycoprotein E-cadherin (E-cadherin-catenin complex) molecules occupy the intercellular space. (2) A mat of actin filaments is located on each of the cytoplasmic surfaces of the zonulae adherentes. The actin filaments are linked to each other via the actin-binding proteins a-actinin and are linked, via another actin-binding protein vinculin, to the protein catenin, which also binds to the intracellular portion of the E-cadherin molecules. It is in this fashion that the E-cadherin molecules are reinforced by the a-actinin filaments of the cytoskeleton. The extracellular moieties of E-cadherins of adjacent cells face each other in the extracellular space and, in the presence of Ca2+ ions, bind to each other, promoting adhesion of adjacent cells to each other. (3) Fasciae adherentes, ribbon-like adhesion zones in the intercalated disks of cardiac muscle, are analogous to zonulae adherentes, but they do not surround the entire perimeter ofthe cardiac muscle cells.

external lamina

The basal lamina in nonepithelial cells is referred to as the

Basal lamina self-assembly is initiated by the polymerization of laminins on the basal cell domain and interaction with the type IV collagen suprastructure.

The constituents of the basal lamina come together in a process of self-assembly to form a sheet-like structure. This process is initiated by both type IV collagen and laminins. The primary sequence of these molecules contains information for their self-assembly (other molecules of the basal lamina are incapable of forming sheet-like structures by themselves). Studies using cell lines have shown that the first step in self-assembly of the basal lamina is calcium-dependent polymerization of laminin molecules on the basal cell surface domain (Fig. 5.31). This process is aided by CAMs (integrins). At the same time, the type IV collagen suprastructure becomes associated with laminin polymers. These two structures are joined together primarily by entactin/nidogen bridges and are additionally secured by other proteins (perlecan, agrin, fibronectin, etc.). The scaffold of type IV collagen and laminins provides the site for other basal lamina molecules to interact and form the fully functional basal lamina.

PDZ-domain proteins

The cytoplasmic portions of all three proteins contain a unique amino acid sequence that attracts regulatory and signaling proteins called ________ These proteins include the zonula occludens proteins ZO-1, ZO-2, and ZO-3 (see Fig. 5.16). Occludin and claudins interact with the actin cytoskeleton through ZO-1 and ZO-3. Regulatory functions during the formation of the zonula occludens have been suggested for all ZO proteins. In addition, ZO-1 is a tumor suppressor, and ZO-2 is required in the epidermal growth factor-receptor signaling mechanism. The ZO-3 protein interacts with ZO-1 and the cytoplasmic domain of occludins. Many pathogenic agents, such as cytomegalovirus and cholera toxins, act on ZO-1 and ZO-2, causing the junction to become permeable.

lamina densa

The lamina densa is a 50-nm-thick dense, flexible feltwork of type IV collagen that is interposed between the lamina lucida and the lamina reticularis. On the lamina lucida side, the lamina densa is coated not only with laminin and entactin but also by perlacan, a proteoglycans that is richly endowed with the glycosaminoglycans heparan sulfate. Laminin binds not only to the integrins and dystroglycans but also to heparan sulfate of perlacan and to type IV collagen of the lamina densa. Moreover, entactin also binds to both laminin and type IV collagen, and in this fashion a strong adhesion is formed between the lamina lucida and the lamina densa, and the sheath of epithelial cells is firmly attached to the basal lamina. The surface of the lamina densa that faces the lamina reticularis is also coated by perlacan as well as another proteoglycans, fibronectin that is synthesized by fibroblasts of the connective tissue. (There is another type of fibronectin, manufactured by cells ofthe liver; see Chapter 10, Blood and Hemopoiesis.)

lamina reticularis

The lamina reticularis is usually 200 nm or more in thickness, and it is composed of type Ill collagen, type VII collagen (anchoring fibrils), type XVIII collagen, and some type I collagen fibers as well as microfibrils (composed of fibrillin). Fibronectin binds to the various types of collagen fibers as well as to the heparan sulfate moieties of perlacan. Additionally, type VII collagen fibrils and microfibrils bind to various components of the lamina reticularis, thereby further securing the lamina densa to the lamina reticularis. Type I and type III collagen fibers loop up from the connective tissue, tethering the lamina reticularis to the superficial surface of the connective tissue. All of these bonds and interactions firmly attach the epithelium to the connective tissue via the various macromolecular components of these structures.

Villin

The major actin-bundling protein of intestinal microvilli.

The molecular structure of type IV collagen determines its role in the formation of the basal lamina network supra- structure.

The type IV collagen molecule is similar to other collagens in that it contains three polypeptide chains. Each chain has a short amino-terminus domain (7S domain), a long middle collagenous helical domain (which interacts with the remaining two chains in the fully assembled molecule), and a carboxy-terminus globular noncollagenous domain (NC1 domain). The six known chains of type IV collagen molecules (a1 to a6) form three sets of triple-helical molecules known as collagen protomers. Th ey are designated as [a1(IV)]2a2(IV); a3(IV)a4(IV)a5(IV); and [a5(IV)]2a6(IV) protomers (see Table 6.2). Protomer assembly begins when the three NC1 domains assemble to form an NC1 trimer (Fig. 5.30). The next step in the assembly of the basal lamina structure is the formation of type IV collagen dimer molecules. This is achieved when two NC1 trimers interact to form an NC1 hexamer. Next, four dimers join in the region of the 7S domain to form a tetramer. The 7S domain of the tetramer (called the 7S box) determines the geometry of the tetramer. Finally, the type IV collagen scaffold is formed when other collagen tetramers interact end to end with each other. This scaffold forms the superstructure of the basal lamina. Assembly of this suprastructure is genetically determined. Those containing [a1(IV)]2a2(IV) protomers are found in all basal laminae. Those containing a3(IV)a4(IV)a5(IV) protomers occur mainly in the kidney and lungs, and those containing [a5(IV)]2a6(IV) protomers are restricted to the skin, esophagus, and Bowman capsule in the kidney.

Laminins in basal lamina

These cross-shaped glycoprotein molecules (140 to 400 kDa) are composed of three polypeptide chains. They are essential in initiating the assembly of the basal lamina. Laminins possess binding sites for different integrin receptors in the basal domain of the overlying epithelial cells. They are involved in many cell- to-extracellular matrix interactions. They also play roles in the development, differentiation, and remodeling of the epithelium. Th ere are approximately 15 different variations of laminin molecules

Focal adhesions are also important sites of signal detection and transduction.

They are able to detect contractile forces or mechanical changes in the extracellular matrix and convert them into biochemical signals. This phenomenon, known as mechanosensitivity, allows cells to alter their adhesion-mediated functions in response to external mechanical stimuli. Integrins transmit these signals to the interior of the cell, where they affect cell migration, differentiation, and growth. Recent studies indicate that focal adhesion proteins also serve as a common point of entry for signals resulting from the stimulation of various classes of growth factor receptors.

ciliogenesis

This process occurs either in the centriolar pathway (by duplication of pairs of existing centrioles, see page 66 in Chapter 2) or more commonly in the acentriolar pathway in which centrioles are formed de novo without the involvement of existing centrioles. Both pathways give rise to multiple procentrioles, the immediate precursors of centrioles. Procentrioles mature (elongate) to form centrioles, one for each cilium, and migrate to the apical surface of the cell. After perpendicularly aligning themselves and securing to the apical cell membrane by alar sheets (transitional fibers), centrioles assume the function of basal bodies. The next stage of ciliary apparatus formation involves the formation of the remaining basal body-associated structures that include basal feet and striated rootlets. From each of the nine triplets that make up the basal body, a microtubule doublet grows upward by polymerization of a- and b-tubulin molecules. A growing projection of the apical cell membrane becomes visible and contains the nine doublets found in the mature cilium. During the elongation stage of motile cilia, the assembly of two single, central microtubules starts in the transitional zone from y-tubulin rings. The subsequent polymerization of tubulin molecules occurs within the ring of doublet microtubules, thus yielding the characteristic axonemal 9 + 2 arrangement. Subsequently, the axoneme grows upward from the basal body, pushing the cell membrane outward to form the mature cilium.

Entactin/nidogen in basal lamina

This small, rod-like sulfated glycoprotein (150 kDa) serves as a link between laminin and the type IV collagen network in almost all basal laminae. Each entactin molecule is organized into distinct domains that bind calcium, support cell adhesion, promote neutrophil chemotaxis and phagocytosis, and interact with laminin, perlecan, fibronectin, and type IV collagen.

how transport of material occurs within the motile cilia

Transport of material occurs within the motile cilia, primary cilia, and flagella referred to as axonemal transport. Within cilia it is known as intraciliary transport, and within flagella it is known as intraflagellar transport. The transport of tubulin dimers and other molecules required by the cilia occurs via carrier proteins, known as raft proteins that pick up cargo, such as tubulin dimers. The raft proteins then become attached to kinesin or to dynein, motor proteins that ferry cargo along microtubules in an anterograde or retrograde direction, respectively. Anterograde is from the basal body toward the tip of the cilium, and retrograde is in the opposite direction, from the tip of the cilium toward the basal body. Defects in the intraciliary transport result in various anomalies, some with even lethal consequences.

Simple acinar

Urethra: paraurethral and periurethral glands Simple acinar glands develop as an outpouching of the transitional epithelium and are formed by a single layer of secretory cells

Occludins

a 60 kDa protein, was the first protein identified in the zonula occludens. It participates in maintaining the barrier between adjacent cells as well as the barrier between the apical and lateral domains. Occludin is present in most occluding junctions. However, several types of epithelial cells do not have occludin within their strands, but they still possess well-developed and fully functional zonulae occludentes.

Polycystic kidney disease (PKD)

a genetic disorder is an autosomal dominant disease occurring in about two per thousand births. There are three mutations responsible for this anomaly, namely PKD - 1, PKD-2, and PKHD-1, but most cases are due to mutations in gene PKD-1 located on chromosome 1 6. For an unknown reason, individuals with these mutations develop abnormal primary centrioles, resulting in abnormal cell cycles as well as defective calcium transport within the cell. During embryonic development, cysts begin forming on the kidneys and increase in size and number. As these cysts continue to gain fluid and become larger, they apply pressure on the uriniferous tubules and prevent them from performing their function. In most patients, the symptoms, such as pain in the back and sides as well as headaches, become evident by the 40th year of life, and eventually, the kidney function of the patients is reduced until they have to be placed on renal dialysis and become eligible for a kidney transplant.

In contrast to H&E (Fig. 5.26a), the periodic acid-Schiff (PAS) staining technique (Fig. 5.26b) results in

a positive reaction at the site of the basement membrane. Although the basement membrane is classically described as exclusively associated with epithelia, similar PAS-positive and silver-reactive sites can be demonstrated surrounding peripheral nerve supporting cells, adipocytes, and muscle cells

primary cilium different

a. The axoneme of primary cilia differs from those of motile cilia in that they possess no central singlets; thus, they have a 9 + 0 configuration; moreover, the central sheet, outer and inner dynein arms, and most radial spokes are absent. b. A set of proteins, known as BBSome (named after Bardet-Biedl syndrome), is located at the distal end of the basal body and is responsible for the formation as well as the proper functioning of the primary cilium. It is the BBSome protein complex that determines which molecules are permitted entry into the cytoplasm of the primary cilium. Disruption of the BBSome is responsible for a number of ciliopathies, including Bardet-Biedl syndrome. c. If a cell leaves the G0 stage of the cell cycle and enters the G1 phase, the primary cilium becomes resorbed, and the basal body returns to its previous function as a centriole. d. Primary cilia of a particular region, such as the kidney tubule or fibroblasts, are oriented in the same direction, and this precise alignment is dictated by the basal foot. This precise alignment permits the primary cilia to perform their functions, whether in the monitoring of the flow of the ultrafiltrate in the kidney tubule or in the migration of fibroblasts in the proper direction during wound healing. e. It has been demonstrated that a number of ion channels and select receptors are present only in the membranes of primary cilia. The specific reason for this exclusivity has not been elucidated, but it is believed that it may have some association with the intraciliary transport mechanism, and disturbances of this particular cellular event are responsible for the various ciliopathies.

Exocrine glands

a. Unicellular glands are composed of a single cell (e.g., goblet cells in tracheal epithelium). b. Multicellular glands (Figure 5.7) (1) Classification is based on two criteria. (a) Multicellular glands are classified according to duct branching as simple glands (duct does not branch) or compound glands (duct branches). (b) They are further classified according to the shape of the secretory unit as an acinar or alveolar (saclike or flasklike) or tubular (straight, coiled, or branched). (2) A connective tissue capsule may surround the gland, or septa of connective tissue may divide the gland into lobes and smaller lobules. (3) Glands may have ducts between lobes (interlobar), within lobes (intralobar), between lobules (interlobular), or within lobules (intralobular), such as striated and intercalated ducts. (4) Multicellular glands secrete various substances. (a) Mucus is a viscous material that usually protects or lubricates cell surfaces. (b) Serous secretions are watery and often rich in enzymes. (c) Mixed secretions contain both mucous and serous components. (5) Mechanisms of secretion vary. (a) In merocrine glands (e.g., parotid gland), the secretory cells release their contents by exocytosis. (b) In apocrine glands (e.g., lactating mammary gland), part of the apical cytoplasm of the secretory cell is released along with the contents. (c) In holocrine glands (e.g., sebaceous gland), the entire secretory cell along with its contents is released.

Microvilli contain a conspicuous core of

about 20 to 30 actin filaments.

Immotile cilia syndrome

absent dynein arm in cilia; sinusitis, infertility, bronchiectasis, situs inversus

Basal bodies are associated with several basal body-associated structures such as

alar sheets (transitional fibers), basal feet, and striated rootlets

With the development of new EM preparation techniques, the lamina lucida appears to be

an artifact of fixation; in the living state, the basal lamina is composed of a single layer of the lamina densa. the tissue specimen for EM is fixed using low-temperature, high-pressure freezing (HPF) methods (without chemical fixatives), it retains much more of the tissue than specimens routinely fixed with glutaraldehyde. EM examination of such specimens reveals that the basal lamina is composed only of the lamina densa. No lamina lucida is detected.

Nectins

are also present in the zonula occludens, and their extracellular domains form a part of the physical barrier

Basal plasma membrane infoldings

are common in ion-transporting epithelia (e.g., distal convoluted tubule of the kidney, striated ducts in salivary glands). 1. They form deep invaginations that compartmentalize mitochondria. 2. Function. They increase the surface area and bring ion pumps (Na+ -K+ adenosine triphosphatase [ATPase]) in the plasma membrane close to their energy supply (ATP produced in mitochondria).

Cilia

are common surface modifications present on nearly every cell in the body. They are hair-like extensions of the apical plasma membrane containing an axoneme, the microtubule-based internal structure. The axoneme extends from the basal body, a centriole-derived, microtubule-organizing center (MTOC) located in the apical region of a ciliated cell. The basal bodies are associated with several accessory structures that assist them with anchoring into cell cytoplasm. Cilia, including basal bodies and basal body-associated structures, form the ciliary apparatus of the cell.

Microvilli

are fingerlike projections of epithelia approximately 1 um long that extend into a lumen and increase the cell's surface area. 1. A glycocalyx (sugar coat) is present on their surfaces (see Chapter I II C). 2. A bundle of approximately 25 to 30 actin filaments runs longitudinally through the core of each microvillus, extending from the tip of the microvillus into the terminal web, a zone of intersecting filaments in the apical cytoplasm. a. The actin filaments within the microvillus are bound to each other by the actin-binding proteins villin, fimbrin, espin, and fascin, and the actin filaments at the perimeter of the actin bundle are affixed to the plasmalemma ofthe microvillus by calmodulin and myosin I. b. The actin filaments are arranged in a specific orientation within the microvillus, so that their plus ends (barbed ends) extend to the tip ofthe microvillus, where they are embedded in an amorphous material known as villin. The minus ends (pointed ends) of the bundle of actin filaments extend into the terminal web of the epithelial cell, where they are affixed to the spectrin and actin filaments of the terminal web. 3. The myosin II and tropomyosin molecules located at the terminal web can interact to contract the apical region of the cell, thereby causing the microvilli to diverge from each other, increasing the intermicrovillar spaces. These enlarged intermicrovillar spaces facilitate the increased transport of materials into the cell. 4. Microvilli constitute the brush border of kidney proximal tubule cells and the striated border of intestinal absorptive cells.

Lateral interdigitations (plicae)

are irregular finger-like projections that interlock adjacent epithelial cells. These lateral interdigitations are most frequently present in cells that function in fluid and/ or electrolyte transport (e.g., epithelial lining of the intestines, proximal tubules of the kidney).

Type II hemidesmosomes

are much simpler than the classical hemidesmosomes, in that they are composed only of the dense cluster of transmembrane proteins ax6b4 integrin whose intracytoplasmic moieties bind to the plakin protein plectin, which in turn binds to the intermediate filaments keratin-8 and keratin-18 (tonofilaments). As in type I hemidesmosomes, the intracytoplasmic components form an electron-dense, plaque-like structure that resembles but is different from the outer dense plaque of a desmosome

actively motile cilia

are processes of the cell that are 7 to 10 um long extending from certain epithelia (e.g., tracheobronchial and oviduct epithelium) that propel substances along their surfaces. They contain a core of longitudinally arranged microtubules (the axoneme), which arises from a basal body during ciliogenesis.

Focal adhesions

are regions of relatively weak anchoring junctions that assist in the attachment of the epithelium to the basal lamina. The principal components are clusters of transmembrane proteins, alpha and beta integrins, whose cytoplasmic moieties are attached to actin filaments of the cytoskeleton via the intracellular anchorage proteins alpha actinin, talin, paxillin, and vinculin, and their extracellular regions are attached to laminin and fibronectin of the basal lamina. Focal adhesions may be attachments of long duration, but mostly they are formed as cells that migrate along the basal lamina surface and continuously detach and reattach during their movement. Both the attachment and the detachment are dynamic processes that occur due to intracellular and/or extracellular signals that alter the three-dimensional conformation of the integrin molecules, causing them to form or break bonds with the intracellular anchorage proteins and with the proteoglycans of the basal lamina.

Cadherins

are represented by transmembrane Ca-dependent CAMs localized mainly within the zonula adherens. At these sites, cadherins maintain homotypic interactions with similar proteins from the neighboring cell. They are associated with a group of intracellular proteins (catenins) that link cadherin molecules to actin filaments of the cell cytoskeleton. Through this interaction, cadherins convey signals that regulate mechanisms of growth and cell differentiation. Cadherins control cell-to-cell interactions and participate in cell recognition and embryonic cell migration. E-cadherin, the most studied member of this family, maintains the zonula adherens junction between epithelial cells. It also acts as an important suppressor of epithelial tumor cells.

Integrins

are represented by two transmembrane glycoprotein subunits consisting of 15 a and 9 b chains. This composition allows for the formation of different combinations of integrin molecules that are able to interact with various proteins (heterotypic interactions). Integrins interact with extracellular matrix molecules (such as collagens, laminin, and fibronectin) and with actin and intermediate filaments of the cell cytoskeleton. Through these interactions, integrins regulate cell adhesion, control cell movement, and shape, and participate in cell growth and differentiation.

Hemidesmosomes

are specialized anchoring junctions whose morphology resembles that of a half of a desmosome. However, instead of attaching cells to each other, hemidesmosomes mediate strong adhesion of epithelial cells to the underlying extracellular matrix (see Figure 5.3). Unlike focal adhesions, hemidesmosomes are mostly of longer duration and provide a firmer attachment of the cell to the basal lamina. Moreover, instead of binding to actin filaments of the cytoskeleton, they are bound to the more robust intermediate filaments.

The mucinogen granules, the secretory product within the cell,

are therefore PAS positive (see Fig. 5.26a). However, they are water-soluble and lost during routine tissue preparation. For this reason, the cytoplasm of mucous cells appears to be empty in H&E-stained paraffin sections. Another characteristic feature of a mucous cell is that its nucleus is usually flattened against the base of the cell by accumulated secretory products (Fig. 5.41).

stereocilia (stereovilli)

are very long (15-20 J.. lm in length) microvilli (they are not cilia) in the hair cells of the inner ear, in the epididymis, and in the vas deferens of the male reproductive tract. The core of the stereocilia is composed of actin filaments that are attached to each other by fimbrin and to the plasmalemma of the stereocilia by villin-2 and ezrin (but not in the hair cells of the inner ear). As in microvilli, the barbed ends of the actin filament bundle extend to the tip of the stereocilia, where villin is absent, and their pointed ends reach and are anchored in the cell web.

CAMs have been identifi ed, and they are classifi ed on the bases of their molecular structure into four major families:

cadherins, integrins, selectins, and the immunoglobulin superfamily

A gap junction is composed of subunits,

called connexons (hemichannels), which extend beyond the cell surface into the gap (a 2-nm-wide intercellular space) (Figure 5.3). Two connexons, one in the plasma membrane of each adjacent cell contacting each other in the intercellular space, form a single gap junction. a. Connexons consist of six subunits (composed of proteins called connexins), which are arranged radially around a central channel with a diameter of 1.5 nm (see Figure 5.3). b. Precise alignment of connexons on adjacent cells produces a junction where they form cell-to-cell channels permitting the passage of ions and small molecules with a molecular weight of less than 1 kDa (kilodaltons) but preventing these molecules from escaping into the extracellular space. c. Since there are different connexons, depending on the amino acid sequence of their connexins, gap junctions may be homotypic or heterotypic. d. Connexins may alter their conformation to shut off communication between cells, especially if one of the cells is dying. e. Usually, a large number of gap junction channels are clustered together to form a gap junction plaque where exchange of ions and small second messenger molecules may occur. f. Connexons are in abundant supply where intercellular communication and coordination is essential such as in smooth and cardiac muscles, nerves, and certain epithelia.

epithelioid tissues

cells are closely apposed to one another but lack a free surface. Although the close apposition of these cells and the presence of a basement membrane would classify them as epithelium, the absence of a free surface more appropriately classifies such cell aggregates as epithelioid tissues. The epithelioid cells are derived from progenitor mesenchymal cells (nondifferentiated cells of embryonic origin found in connective tissue).

The intramembrane strands that close off the paracellular route possess four groups of transmembrane proteins (tight junction)

claudins, occludins, nectins, junctional adhesive molecules (JAMs). These four proteins have to be reinforced so that they maintain their proper position, and this reinforcement is due to the presence of actin filaments (F-actin) of the cytoskeleton. However, there are intermediary proteins that are capable of binding both to F-actin as well as to the four proteins just described. These are the three zonula occludens proteins, Z0-1, Z0-2, and Z0-3, as well as a fourth protein, known as afadin. These four intermediary proteins are located on the cytoplasmic aspect of the region of the cell membrane involved in the formation of the tight junction and, in that fashion, are interposed between the F-actin and the claudins, occludins, nectins, and JAMs, forming a strong bond that maintains the integrity of the tight junction

acini

clusters of secretory cells that produce zymogen granules containing proenzymes Serous cell-containing acini (sing., acinus) are found in the parotid gland and pancreas. Acini of some glands, such as the submandibular gland, contain both mucous and serous cells. In routine tissue preparation, the serous cells are more removed from the lumen of the acinus and are shaped as crescents or demilunes (half-moons) at the periphery of the mucous acinus

Epithelioid patterns are also formed by accumulations of

connective tissue macrophages in response to certain types of injury and infections as well as by many tumors derived from epithelium.

axoneme

consists of 9 doublet microtubules uniformly spaced around 2 central microtubules (9 + 2 configuration), where each doublet microtubule is composed of a complete microtubule, referred to as microtubule A that consists of the normal 13 protofilaments, and an incomplete microtubule, known as microtubule B consisting of only 10 protofilaments. Microtubule A shares three of its protofilaments with microtubule B so that microtubule B has a completely closed structure. Each central microtubule consists of 13 proto filaments. Cilia have the following additional components: (1 ) Inner and outer ciliary dynein arms, which extend unidirectionally from one member of each doublet microtubule and interact with adjacent doublets, so that they slide past one another. These arms consist of ciliary dynein, with ahead, that is, an ATPase that splits ATP to liberate the energy necessary for the active movement of a cilium. (2) Radial spokes that extend from each of the nine outer doublets toward the central sheath. (3) Central sheath, which surrounds the two central microtubules; this sheath and the radial spokes regulate the ciliary beat. (4) Nexin, an elastic protein that connects adjacent doublet microtubules to each other and helps to maintain the shape of the cilium. (5) Tektin, proteins that resemble intermediate filaments and form physical support to the axoneme by forming linear backbones that attach at the outer aspects (away from the central sheet) of the junction of each microtubule A with its microtubule B.

Claudins

constitute a family of proteins (20 to 27 kDa) that have recently been identified as integral components of zonula occludens strands. Claudins form the backbone of each strand. In addition, claudins (especially claudin-2 and claudin-16) are able to form extracellular aqueous channels for the paracellular passage of ions and other small molecules. About 24 different members of the claudin family have been characterized to date. Mutations in the gene encoding claudin-14 have been recently linked to human hereditary deafness. A mutated form of claudin-14 causes an increased permeability of zonula occludens in the organ of Corti (receptor of hearing), affecting generation of action potentials.

The transcription factor Math1

expressed in the intestinal epithelium determines the fate of the cell. The cells committed to the secretory lineage (i.e., they will differentiate into goblet, enteroendocrine, and Paneth cells) have increased expression of Math1. Inhibition of Math1 expression characterizes the default developmental pathway into absorptive intestinal cells (enterocytes)

Selectins

expressed on white blood cells (leukocytes) and endothelial cells and mediate neutrophil-endothelial cell recognition. This heterotypic binding initiates neutrophil migration through the endothelium of blood vessels into the extracellular matrix. Selectins are also involved in directing lymphocytes into accumulations of lymphatic tissue (homing procedure).

Stereocilia of the sensory epithelium of the ear

exquisitely sensitive to mechanical vibration and serve as sensory mechanoreceptors rather than absorptive structures. They are uniform in diameter and organized into ridged bundles of increasing heights, forming characteristic staircase patterns (Fig. 5.5a). Their internal structure is characterized by the high density of actin filaments extensively cross-linked by espin, which is critical to normal structure and function of stereocilia. Stereocilia of sensory epithelia lack both ezrin and a-actinin.

The actin filaments inside the microvillus are cross-linked at 10-nm intervals by other actin-bundling proteins such as

fascin (57 kDa), espin (30 kDa), fimbrin (68 kDa).

induced pluripotent stem (iPS) cells

from human keratinocytes demonstrates that somatic adult cells can be reprogrammed to a pluripotent state by the enforced expression of several embryonic transcription factors. Keratinocyte-derived iPS cells appear to have identical morphological and functional characteristics to human embryonic stem cells. In the future, iPS cells may play an important role for both custom-tailored cell therapy (homologous cell recombination and transplantation) and disease modeling. This involves generating iPS cells from a patient's epidermis, which can be further diff erentiated in vitro into disease-affected cell types and tested for responses to novel drug therapies.

Type I hemidesmosomes

have several components, namely the dense cluster of transmembrane proteins a6b4 integrin, whose intracytoplasmic moieties bind to the protein erbin and the plakin proteins plectin and bullous pemphigoid antigen 230 (BP230). It is these two plakin proteins that connect a6b4 integrins to the intermediate filaments (keratin-5 and keratin-14, also known as tonofilaments). Erbin assists in the binding of the integrin molecule to BP230. Two additional proteins are associated with the a6 component of the integrin, namely bullous pemphigoid antigen 180 (BP 180, also known as type XVII collagen) and cluster of differentiation protein 151 (CD151). BP 180 binds intracellularly to both the a6 component of the integrin and to plectin, and extracellularlyto the a6 component of the integrin and to laminin of the basallamina. The extracellular moieties of ab4 integrins also bind to the laminins and type IV collagens of the basal lamina. CD151 functions to ensure that enough integrin molecules are recruited to the area so that hemidesmosome formation can occur. The intracytoplasmic components of the hemidesmosome form an electron-dense, plaque-like structure that resembles but is different from the outer dense plaque of a desmosome.

Keratin filaments (tonofilaments)

in the cell terminate in the hemidesmosome plaque, allowing these junctions to link the cytoskeleton with the components of the extracellular matrix.

Junctional adhesion molecule (JAM)

is a 40 kDa protein that belongs to the immunoglobulin superfamily (IgSF). JAM does not itself form a zonula occludens strand but is instead associated with claudins. It is involved in the formation of occluding junctions in endothelial cells as well as between endothelial cells and monocytes migrating from the vascular space to the connective tissue.

basal body

is a cylindrical structure at the base of each cilium that consists of nine triplet microtubules arranged radially in the shape of a pinwheel . (9 + 0 configuration). It resembles a centriole (see Figure 5.6) but has a less complex central organization. The inner two triplets of the basal body give rise to the doublet microtubules of the cilium axoneme. The outermost, third microtubule, referred to as microtubule C, of the triplet is also incomplete. It is composed of only 10 protofilaments and shares 3 of microtubule B's protofilaments so that microtubule C is also a completely closed structure. The region where the basal body and the axoneme merge with each other is frequently referred to as the transition zone. It is the basal body and structures coupled with it that not only secure the cilium to the cell but also function in ensuring that all cilia of the cell beat in the same direction. Structures that are associated with the basal body are the alar sheet, basal feet, and striated rootlets.

Bardet-Biedl syndrome

is a disorder due to disruptions in the normal functioning of BBSome located at the base of the basal body of the primary cilium. The manifestations of this syndrome are varied and include night blindness, speech disorder, malformations of the rods and cones of the retina with a subsequent loss of vision, presence of extra digits on the hands and feet, kidney failure, urogenital defects, and obesity. Many patients succumb to kidney failure.

The basement membrane

is a narrow, flexible, PAS-positive (i.e., it stains purplish with periodic acid-Schiff reagent) acellular supportive structure that is consistently interposed between the epithelium and the underlying connective tissue. The thickness of the basement membrane depends on its location, so that it is much thicker in thick skin than in the lining of the trachea, but on the average it is usually 0.3 Jlm wide. When viewed with the electron microscope, the basement membrane is resolved to be composed of two layers, the basal lamina, approximately 100 nm in thickness, and the lamina reticularis, which is at least 200 nm in thickness (Figure 5.4).

fascia adherens

is a sheet-like junction that stabilizes nonepithelial tissues. Physical attachments that occur between cells in tissues other than epithelia are usually not prominent, but there is at least one notable exception. Cardiac muscle cells are arranged end to end, forming thread-like contractile units. The cells are attached to each other by a combination of typical desmosomes, or maculae adherentes, and broad adhesion plates that morphologically resemble the zonula adherens of epithelial cells. Because the attachment is not ring-like but rather has a broad face, it is called the fascia adherens (Fig. 5.20). At the molecular level, the structure of the fascia adherens is similar to that of the zonula adherens; it also contains the zonula occludens ZO-1 protein found in the tight junctions of epithelial cells.

Bullous pemphigoid

is an autoimmune disease in which antibodies against hemidesmosomes are produced. 1 . This disease is chara cterized by chronic genera lized blisters in the skin. 2. These blisters cause the epithelium to separate from the underlying substratum.

The junctional complex

is an intricate arrangement of membrane-associated cell adhesion molecules that function in cell-to-cell attachment of columnar epithelial cells. It corresponds to the terminal bar observed in epithelia by light microscopy and consists of three distinct components that are visible by electron microscopy

The basal lamina

is manufactured by the epithelial layer and is composed of two regions, the electron-lucent lamina Iucida, which is in direct contact with the basal plasma membrane of the epithelial cells, and the electron-dense lamina densa, which is located between the lamina lucida and the lamina reticularis. Although some authors now believe the lamina lucida to be a fixation artifact and suggest that the lamina densa constitutes the entirety of the basal lamina, the research results are inconclusive enough that in this textbook both the components are detailed.

A single nonmotile cilium (primary cilium)

is present on nearly every human cell that is in the G0 stage of the cell cycle. These structures were believed to be nonfunctional evolutionary remnants, but recently it has been demonstrated that they have essential functions in the organization of signaling pathways not only during embryonic development but also in the adult organism. It has been amply demonstrated that impaired primary cilia are responsible for various anomalous conditions, known as ciliopathies

Endothelium

is the epithelial lining of the blood and lymphatic vessels.

Endocardium

is the epithelial lining of ventricles and atria of the heart.

Mesothelium

is the epithelium that lines the walls and cov- ers the contents of the closed cavities of the body (i.e., the ab- dominal, pericardial, and pleural cavities;)

terminal web

layer inside plasma membrane in cells forming a layer or lining is composed of actin filaments stabilized by spectrin (468 kDa), which also anchors the terminal web to the apical cell membrane (Fig. 5.3b)

serous membrane (serosa)

lines the peritoneal, pericardial, and pleural cavities. These cavities are usually described as closed cavities of the body, although in the female, the peritoneal cavity communicates with the exterior via the genital tract. Structurally, the serosa consists of a lining epithelium, the mesothelium, a supporting connective tissue, and a basement membrane between the two. Serous membranes do not contain glands, but the fluid on their surface is watery.

Endocrine glands

may be unicellular (e.g., individual endocrine cells in gastrointestinal and respiratory epithelia) or multicellular (e.g., adrenal gland), and they lack a duct system. In multicellular glands, secretory material is released into fenestrated capillaries, which are abundant just outside the basal lamina of the glandular epithelium.

The tight junction prevents

not only the movement of substances into the extracellular space from the lumen but also intermingling of the transmembrane proteins of the apical with those of the lateral domains. This ability (its tightness) is directly related to the number and complexity of the intramembrane strands and to the function of the epithelia housing the particular tight junction.

Epithelial cell tumors

occur when cells fail to respond to normal g rowth regulatory mechanisms. a. These tumors a re benign when they remain local. b. They a re malignant when they invade neighboring tissues. Then they may (or may not) metastasize to other parts of the body. i. Carcinomas a re malignant tumors that a rise from surface epithelia. ii. Adenocarcinomas are malignant tumors that a rise from glands.

Anchoring junctions

of epithelial cells consist of four types, two on the cell's lateral domain, zonula adherens (plural: zonulae adherentes) and desmosome (macula adherens; plural: maculae adherentes) and two, discussed in the section below, on the cell's basal domain, namely hemidesmosomes and focal adhesions

Conformational changes in connexins leading to

opening or closing gap junction channels have been observed with atomic force microscopy. Channels in gap junctions can fluctuate rapidly between an open and a closed state through reversible changes in the conformation of individual connexins. The conformational change in connexin molecules that triggers closure of gap junction channels at their extracellular surface appears to be induced by Ca ions (Fig. 5.23). However, other calcium-independent gating mechanisms responsible for closing and opening of the cytoplasmic domains of gap junction channels have also been identified.

In humans, mutations in two genes, ADPKD1 and ADPKD2, appear to affect development of these primary cilia, leading to

polycystic kidney disease (PKD). The proteins encoded by these genes, polycystin-1 and polycystin-2, respectively, are essential in the formation of the calcium channels associated with primary cilia (see Fig. 5.10b). This autosomal recessive disorder is characterized by multiple expanding cysts in both kidneys, which ultimately destroy the renal cortex and lead to renal failure. However, individuals with PKD often exhibit other pathologies not associated with the kidney that are now attributed to ciliary abnormalities. These include cysts in the pancreas and liver that are accompanied by enlargement and dilatation of the biliary tree system. Other changes include retinitis pigmentosa (abnormalities of the photoreceptors cells of the retina that cause progressive vision loss), sensorineural hearing loss, diabetes, and learn- ing disabilities. The knowledge of the distribution of primary cilia in the body may help to explain the crucial role of these once-forgotten cellular projections in the normal function of many vital internal organs.

In contrast to mucus-secreting cells, serous cells produce

poorly glycosylated or nonglycosylated protein secretions. The nucleus is typically round or oval (Fig. 5.42). The apical cytoplasm is often intensely stained with eosin if its secretory granules are well preserved. The perinuclear cytoplasm often appears basophilic because of an extensive rough endoplasmic reticulum, a characteristic of protein-synthesizing cells.

Permeability of the zonula occludens depends not only on the complexity and number of strands but also on the

presence of functional aqueous channels formed by various claudin molecules. However, in some epithelial cells, the number of strands does not directly correlate to the tightness of the seal. Differences in tightness between different zonulae occludentes could be explained by the presence of aqueous pores within individual zonula occludens strands (Fig. 5.17b). Recent experiments indicate that claudin-16 functions as an aqueous Mg channel between specific kidney epithelial cells. Similarly, claudin-2 is responsible for the presence of high-conductance aqueous pores in other kidney epithelia. Claudins not only form the backbone of the individual zonula occludens strand but also are responsible for the formation of extracellular aqueous channels. Thus, the combination and mixing ratios of claudins to occludins and other proteins found within individual paired zonula occludens strands determine tightness and selectivity of the seal between cells.