Epithelial Cell Domains Charles L. Hitchcock, MD, PhD Department of Pathology

Primary Learning Objective Compare and contrast the normal morphologic features of epithelial tissue with the specific morphologic changes associated with disease.

Secondary Learning Objectives Identify the morphologic features of the apical domains of epithelial cells from an image or description. Compare and contrast the location and molecules making up the junctional complexes in the lateral domains of epithelial cells from an image or description. Describe the structure and functions of the molecules involvement in epithelial cell-basement membrane binding.

Cellular Domains

Objective 1 Identify the morphologic features of the apical domains of epithelial cells from an image or description.

Apical Domain Surface: Enzymes, ion channels, and carrier proteins Specialized structures Microvilli Cilia – motile and non-motile Stereocilia

Microvilli Finger-like extensions of the plasma membrane of apical epithelial cell. “Brush boarder” – renal tubules “Striated border” – intestines Their core contains cross- linked actin filaments. Movement due to terminal web contraction. Microvilli Microvilli Movement Microvilli Structure

Motile Cilia Ciliated Respiratory Epithelium GC Loose Connective Tissue Microtubule c

Rare autosomal recessive Reduction in dynein arms; lack central tubules; 8-1 doublet pattern, etc. leads to an uncoordinated beating of the cilia. Chronic bronchitis and sinusitis, pneumonia, otitis media, hearing loss, male infertility due to an immotile cilia on sperm. Situs inversus, Primary Cilia Dyskinesia (Kartagener Syndrome)

Primary Cilia

Summary – Apical Domain Surface enzymes, ion channels, and carrier proteins Microvilli – increase area for absorption – intestine and renal tubules Motile cilia – respiratory epithelium –9-2 configuration of microtubule doublets –A and B microtubules with two dynein arms forming cross-bridges from the A microtubule to an adjacent B microtubule –Primary Cilia Dyskinesia –loss of dynein bridges – situs inversus, sinusitis, immotile sperm, URI and LRI Non-motile cilia –in kidneys respond to fluid flow as a mechanoreceptors and calcium ion channels – gene mutations lead to cyst formation

Objective 2 Compare and contrast the location and molecules making up the junctional complexes in the lateral domains of epithelial cells from an image or description.

Epithelial Cell Lateral Domains

Zonula Occludens - (Tight Junctions)

Zonula Adherens

Macula Adherens (Desmosome) Keratin filaments Cadherins - desmoglein desmocollin Dense plaque - Desmoplakin Plakoglobin

Gap Junctions (Communicating Junctions) cAMP Ca +2 Connexon - 6 connexin proteins

Summary – Lateral Domain Junctional Complexes Zonula occludens - apical, belt-like continuous barrier, occuldin and claudins are critical proteins Zonula adherens – belt-like structure, link cytoplasmic actin network via E-cadherins attached to alpha-actinin and vinculin plaque just below the plasma membrane Macula adherens - “spot welds”, desmoglein and desmocollin homodimers that link cytoplasmic keratin intermediate filaments networks of adjacent cells via desmoplakin and plakoglobin containing dense plaques. Gap junctions - connexin containing pores that provide rapid intercellular movement of ions and small signalling molecules.

Cell Adhesion Molecules Transmembrane proteins Separate extracellular cytoplasmic and binding domains Extracellular binding domain can be calcium dependent or independent Link cytoskeletal systems between cells Involved in signal transduction

Cadherins Transmembrane homodimers Links to actin or intermediate filaments calcium dependent binding, Altered in tumor progression

Selectins Binds to specific carbohydrate on surface glycoproteins and glycolipids Binding is calcium dependent Cytoplasmic tail in linked to actin cytoskeleton Functions in leukocyte homing

Immunoglobulin Superfamily Immunoglobulin-like molecules Homophilic and heterophilic binding that is calcium independent (..CAMs and CD designations) Leukocyte adhesion, neurite growth, and myelination CD4 is the receptor of HIV

Integrins Heterodimeric transmembrane proteins Cell-cell and cell-ECM calcium independent binding Facilitate cell movement in the ECM and two-way signalling In hemidesmosomes,

Summary – Lateral Domain Cell Adhesion Molecules Cadherins – homodimeric proteins, calcium dependent homophilic binding, linking actin or cytoskeletal filament networks of adjacent cells Selectins – heterophilic binding to specific carbohydrates on cell surface glycoproteins and glycolipids, links to actin filament network, leukocyte homing and transmigration Immunoglobulin superfamily – Homophilic binding and heterophilic binding to integrins, leukocyte binding Integrins – heterodimeric transmembrane, proteins, heterophilic binding of ECM adhesive proteins, to linked to actin cytoskeleton, signal proteins, hemidesmosomes, and cell motility.

Objective 3 Describe the structure and functions of the molecules involvement in epithelial cell-basement membrane binding.

Basement Membrane Basal Lamina Reticular Lamina collagen fibers PAS Stain Renal Tubules Electron Micrograph of the Basement Membrane

Basal Lamina Components 3D lattice of extracellular matrix components Collagens – Type IV predominates, Type VII anchoring fibrils attach to hemidesmosomes. Multiadhesive proteins – laminin 5, fibronectin, entactin Proteoglycans – most of the basal lamina volume

Hemidesmosome

Focal Adhesions

Clinical Relevance Pemphigus vulgaris IgG to desmoglein 3 Pemphigus folaceous IgG to desmoglein-1

Clinical Relevance Mutations of hemidesmosomal proteins associated with epidermolysis bullosa (EB) variants –COL7A1 - dystrophic EB- severe blistering apparent from birth – with loss of tethering of basement membrane to dermal matrix –Cytokeratins filaments – epidermolytic EB –Laminin and integrins – junctional EB Autoantbodies to hemidesmosomal proteins gives rise to bullous pemphigoid –IgG to BP180 and BP230 proteins

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