2009 Lecture 8

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Epithelial Cell Junction Types

Contents

Cell Junctions

Introduction

Lets stick together!

This lecture introduces the concept of cell adhesion. Unicellular organisms use to adhere to the environment, nutrition or pathogenesis. Multicellular organisms require adhesion for cells to adhere to each other and the extracellular matrix. Cell adhesion occurs through specific cellular specializations and molecules and has both static and dynamic functions. This topic will be revisited in lectures on extracellular matrix, cell cytoskeleton and signalling.

Dr Mark Hill (2009)

Lecture Audio

The University has a system for automated recording of lectures called Lectopia. Lectopia requires login using your student number and unipass. I will be adding the link to each iLecture Audio following the Lecture. Due to the automated recording method, most lectures begin 4-5 minutes into MP3 recordings and occasionally stop before the end of the lecture. 2009 All Audio Files

Lecture 8: Cell Adhesion Lecture Date: 01-04-2009 Lecture Time: 10:00 Venue: BioMed E Speaker: Mark Hill

Archive

MH - note that content listed below will not match exactly current lecture structure and has been selected as having similar content.

Objectives

Desmosome
  • Broad understanding of cell adhesion with other cells and extracellular matrix
  • Understanding of different adhesion proteins
  • Understanding of different forms of adhesion junctions
  • Understanding of biological role of adhesion
  • Brief understanding of adhesion abnormalities

History

Below are some example historical research finding related to cell junctions from the JCB Archive. 1963 Defining junctional complexes A mess of nomenclature is sorted out by Marilyn Farquhar and George Palade, who use superb microscopy to define three of the four major types of cell–cell junctions in the polarized epithelial cells of vertebrates.

Epithelial Cell Junctions

1967 Defining gap junctions Jean-Paul Revel and Morris Karnovsky unite the fields of adhesion and intercellular current transfer around a distinct, structural correlate called the gap junction.

1967 Endothelial tight junctions form the blood–brain barrier What is the cellular correlate of the so called blood-brain barrier? Thomas Reese and Morris Karnovsky find that it is the junctions between endothelial cells in the brain vasculature. Their discovery comes thanks to three factors: high resolution electron microscopy; the development of sensitive tracer methods; and a fortuitous lunch date.

1977 The sticky business of discovering cadherins A change in the recipe for a trypsin solution allows Masatoshi Takeichi to distinguish calcium-dependent adhesion.

1984 Sticking it out with tight junctions With persistence and a species change, tight junction proteins are isolated.

Why Adhesion?

  • Adhesion refers to “stickiness”
  • Evolution of multicellular organisms developed specialized cells and tissues
  • Embryonic development also allows differentiation of different cell/tissue types
  • Interaction between cell-cell and cell-extracellular matrix by specific contacts
  • Note the Cell Biology definition is different from the Clinical term
    • Clinical term “adhesions” bands of scar-like tissue forming between two surfaces inside the body

Types of Junctions

Epithelia jns1.jpg

Prokaryotes

Bacteria adhesin.gif

  • Prokaryotes adhesion molecules usually termed "adhesins"
  • occur on pili (fimbriae), flagellae, or the cell surface
  • adhesion first step in colonization


Unicellular Eukaryotes

  • express multiple adhesion molecules for nutrition, migration and pathogenesis
  • malarial parasite (Plasmodium falciparum) uses circumsporozoite protein, an adhesion molecule, to bind to liver cells
  • merozoite surface protein to bind red blood cells


Multicelluiar Eukaryotes

  • Maintains body form and structure
  • Tissues organized during development
  • Can be used for cell migration
  • Cell signalling Alteration in disease


Types of Adhesion

  • Cell-cell
  • Cell-extracellular matrix

Cell adhesion summary.png

Adhesive Functions

  • Basal lamina assemble and organize epithelia
  • Smooth muscle
    • Maintains integrity during contraction
  • Binds growth factors
    • Neurons growth cone guidance, fasiculation
  • Cell Migration
    • Development - migration, cell sorting, tissue development
    • Transmigration, wound healing, macrophages

Tem transmigration1.jpg Transmigration1.jpg


Links: Transmigration Movie

Adhesion Characteristics

Transmembrane glycoproteins Normally permanent Except migrating cells and embryonic Changes with development Loose adhesion when mature or disease Erythrocytes, cancer


Types of Adhesion Molecules

Cadherins Immunoglobulin Superfamily Selectins Gap Junctions Integrins


Cadherins

Cadherin2.gif

  • vertebrates have 20+, separate gene loci
  • E-cadherins (epithelial cells)
  • N-cadherins (nerve and muscle)
  • P-cadherins (placenta and epithelial)

Cadherin2.gif

  • Contain 5 cadherin repeats
  • Each comprising sandwich of beta sheets

requires calcium ions to bind Homophilic binding through end element Like with like Functional unit a dimer

Cadherins Clustering Important for function Multiple dimer interactions possible occur in desmosomes Protocadherins lack interface for homophilic adhesiveness found in cadherins, and have structural loops specific to the protocadherin family role unknown (develoment? tissue morphogenesis, formation of neuronal circuits) 6 cadherin repeats (PMID:18050421)


Immunoglobulin Superfamily

Igsuperfamily.gif Vertebrates have 100+ In addition to adhesion they also have role in immune system Contain varying number of Ig-related domains

G. Edelman Nobel Prize in Physiology or Medicine in 1972 "for their discoveries concerning the chemical structure of antibodies" studying the nervous system Cell Adhesion Molecules (CAMs) family Neuronal cell adhesion molecules (N-CAM) N-CAM, Ng-CAM L-CAM, I-CAM


http://nobelprize.org/nobel_prizes/medicine/laureates/1972/index.html Neuronal cell adhesion molecules

(Image: Stress, cognitive impairment and cell adhesion molecules, Carmen Sandi, Nature Reviews Neuroscience 5, 917- (December 2004) doi:10.1038/nrn1555)


Selectins

Igsuperfamily.gif Vertebrates have only in circulatory system Role in adhesion of leukocytes (blood cells) to endothelium (vessel wall) Cooperate with integrins and Ig-SF receptors Selectins 2 Heterophilic interactions Bind counterreceptors


Integrins

Integrin.gif

  • Mammals have genes for 18 alpha and eight beta integrins
  • Role in cell adhesion to extracellular matrix (ECM) basement membranes
  • Induction of cell polarization by adhesion
  • Cell migration through ECM will discuss in ECM lecture
  • Glycosylated proteins
  • Bind through C terminal lectin domain of selectin
  • Comprising sandwich of beta sheets
  • Held together by hydrophobic interactions

Integrin.gif

  • Mainly receptors for ECM proteins
  • Fibronectin, laminin, collagen
  • Some heterotypic binding Ig superfamily
  • Interact with cell cytoskeleton
  • key component in signalling

Cell Junction Types

  • Desmosomes (macula adherens)
  • Adherens Junctions (zonula adherens)
  • Septate Junctions
  • Tight Junctions
  • Gap Junctions


Desmosomes

Desmosome1.jpg

  • Discovered by K.R. Porter in 1954
  • intermediate filaments anchor the dense plaque that occurs under the membrane of each cell
  • desmos = bond
  • skin, lining of internal body cavity surfaces
  • disappear when cells are transformed

Desmosome1.jpg

Hemi-Desmosome

cell anchored to extracellular matrix Present in tissues subject to shear or lateral stress Hemi=half

Adherens Junctions

microfilaments anchor the plaque that occurs under the membrane of each cell plaques not as dense also occur as hemiform heart muscle, layers covering body organs, digestive tract transmembrane proteins Cadherin

Septate Junctions

Discovered by R.L. Wood 1959 found in invertebrate tissues adhesion, sealing, communication septa = walls regularly spaced cross bars 15-17 nm

Tight Junctions

Tight junction3.jpg

Discovered by M.G. Farquhar and G.E. Palade in 1963 zonula occludens Fusion of 2 plasma membranes acts as a “seal” Epithelia lining digestive system gut, ducts, cavities of glands, liver, pancreas capillary walls urinary bladder

Gap Junctions

  • Discovered by J.P. Revel & M.J. Karnovsky in 1967
  • allowing direct communication between cells (open & close)
  • close membranes 2 - 3 nm apart
  • connexins form hollow 1.5 nm diameter cylinders
  • heart muscle, smooth muscle electrical and chemical integration as a single functional unit
  • Also in embryonic development

Gap junction1.jpg


  • two hemichannels (connexons)
  • each formed from 6 connexin molecules
  • rapidly turned over

Gap junction5.jpg

Junctions Overview - Typical Epithelia

Tight Junction

seals neighbouring cells

Adherens Junction

joins actin bundles between cells

Desmosome

joins intermediate filaments between cells

Gap Junction

cell-cell communication, passage of small molecules

Hiemidesmosome

anchors cell intermediate filaments to to basal lamina (extracellular matrix)


Extracellular Matrix

Substances secreted by cells lying outside the cell membrane Exocytosis Adhesion cell ecm2.jpg

Integrins

Mammals have genes for 18 alpha and eight beta integrins Role in cell adhesion to extracellular matrix (ECM) basement membranes Induction of cell polarization by adhesion Cell migration through ECM Mainly receptors for ECM proteins Fibronectin, laminin, collagen Some heterotypic binding Ig superfamily Interact with cell cytoskeleton signalling


Focal Adhesions

Adhesion cell ecm2.jpg

links the outside of the cell (ECM) through transmembrane proteins (integrins) with the cell cytoskeleton (actin microfilaments) extracellular matrix integrins actin cytoskeleton Fl focaladhesion.jpg

Abnormalities

Desmosomes

Adhesion cell ecm2.jpg

pemphigus and bullous impetigo- antibodies made against one of their own desmosomal cadherin proteins

antibodies bind to and disrupt the desmosomes that hold together skin epithelial cells

severe skin blistering, leakage of body fluids

palmoplantar keratoderma

Arrhythmogenic right-ventricular cardiomyopathy (ARVC)

Oncogenesis

not the cause but transformed cells loose adhesion, able to "break away" and spread (metastisis).

Links: Cadherin Knockouts | human desmosomal disorders | NCBI - Genes and Diseases | NCBI - OMIM |

References

Textbooks

Essential Cell Biology

  • Chapter 19 Tissues Epithelial sheets and Cell-Cell Junctions p606

Molecular Biology of the Cell

Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter New York and London: Garland Science; c2002

  • Molecular Biology of the Cell 4th ed. - V. Cells in Their Social Context Chapter 19. Cell Junctions, Cell Adhesion, and the Extracellular Matrix
  • Cell Junctions


Molecular Cell Biology

Lodish, Harvey; Berk, Arnold; Zipursky, S. Lawrence; Matsudaira, Paul; Baltimore, David; Darnell, James E. New York: W. H. Freeman & Co.; c1999

The Cell- A Molecular Approach

Cooper, Geoffrey M. Sunderland (MA): Sinauer Associates, Inc.; c2000

Search Online Textbooks

Books

PubMed

  • PubMed is a service of the U.S. National Library of Medicine that includes over 18 million citations from MEDLINE and other life science journals for biomedical articles back to 1948. PubMed includes links to full text articles and other related resources. PubMed
  • PubMed Central (PMC) is a free digital archive of biomedical and life sciences journal literature at the U.S. National Institutes of Health (NIH) in the National Library of Medicine (NLM) allowing all users free access to the material in PubMed Central. PMC
  • Online Mendelian Inheritance in Man (OMIM) is a comprehensive compendium of human genes and genetic phenotypes. The full-text, referenced overviews in OMIM contain information on all known mendelian disorders and over 12,000 genes. OMIM
  • Entrez is the integrated, text-based search and retrieval system used at NCBI for the major databases, including PubMed, Nucleotide and Protein Sequences, Protein Structures, Complete Genomes, Taxonomy, and others Entrez

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Reviews

  • Tight junctions/adherens junctions: basic structure and function. Niessen CM. J Invest Dermatol. 2007 Nov;127(11):2525-32. Review.. PMID: 17934504
  • The desmosome and pemphigus. Waschke J. Histochem Cell Biol. 2008 Jul;130(1):21-54. Epub 2008 Apr 3. Review. PMID: 18386043


Articles

Working Area

Adhesion Images

A series of micrographs showing adhesion junction images. Adhesion Junction Images | Cell Biology Images | New Images

There is also a gallery of all images added sorted by date New Images (the search option will only search by image file name).

2009 Course Content

Lectures

Cell Biology Introduction | Cells Eukaryotes and Prokaryotes | Cell Membranes and Compartments | Cell Nucleus | Cell Export - Exocytosis | Cell Import - Endocytosis | Cell Mitochondria | Cell Junctions | Cytoskeleton Introduction | Cytoskeleton 1 Intermediate Filaments | Cytoskeleton 2 Microtubules | Cytoskeleton 3 Microfilaments | Extracellular Matrix 1 | Extracellular Matrix 2 | Cell Cycle | Cell Division | Cell Death 1 | Cell Death 2 | Signal 1 | Signal 2 | Stem Cells | Stem Cells | Development | Revision

Laboratories

Introduction to Lab | Microscopy Methods | Preparation/Fixation | Immunochemistry | Cell Knockout Methods | Cytoskeleton Exercise | Confocal Microscopy | Tissue Culture 1 | Tissue Culture 2 | Microarray Lab visit

Dr Mark Hill 2013, UNSW Cell Biology - UNSW CRICOS Provider Code No. 00098G