Epithelial Cell Domains

Charles L. Hitchcock, MD, PhDDepartment 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

MicrovilliStructure

Motile CiliaCiliated Respiratory Epithelium

GCGC

GC

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 1 Quiz

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 -desmogleindesmocollin

Dense plaque -

DesmoplakinPlakoglobin

Gap Junctions (Communicating Junctions)

cAMP

Ca+2

Connexon -6 connexinproteins

Summary – Lateral DomainJunctional 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 DomainCell 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 2 Quiz

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 vulgarisIgG to desmoglein 3

Pemphigus folaceousIgG 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

Objective 3 Quiz

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