Cell-Cell Adhesion and Development

Differential Adhesion Hypothesis

• Malcolm Steinberg (1964)

• Cells actively move to create tissue organization

  • Rearrange themselves to most thermodynamically stable pattern

  • Changes in gene activity change the cell surface

    • Must restore new thermodynamic equilibrium

Tight junctions:

• prevent flow of liquid from inside the gut to the cells below

Gap junctions

• used in cell-cell communications

Adherens junctions

• connect actin cytoskeleton from one cell to the next

Desmosomes

• connect intermediate filaments

Hemidesmosomes

connect intermediate filaments to the basal lamina/basement membranes

Cadherin molecules

• Calcium-dependent-adhesion molecules

• Crucial for spatial segregation of cell types

• Interact with other cadherins on adjacent cells

• Anchored into cell by protein complex (catenins)

• Expression patterns change over time

  • Timing of developmental events can depend on cadherin expression

• Type and amount of cadherin important in cell sorting

E-cadherin

Early embryonic cells

N-cadherin:

Nervous system

P-cadherin

 Placenta

R-cadherin

Retina formation

Protocadherins

not attached to the actin cytoskeleton, important in moving cells

Gap Junctions are

• Communication channels between adjacent cells

  • Can receive small, soluble signaling molecules through the membrane

  • Made of connexin proteins

Cell Migration is done by

Epithelial and mesenchymal cells

• Migration requirements

• Polarization

• Protrusion of leading edge

• Adhesion

• Release of adhesion

Regulation of Cell Movement

• Rac and Rho proteins

  • GTP binding proteins

  • Respond to paracrine signals

• Bind to actin and myosin, change actin cytoskeleton

• Form pseudopodia and lamellipodia at the leading edge

• Stress fibers monitor cell shape changes on trailing edge

Movement and Wnt Pathway

• Disheveled binds Rac and Rho

• Rac and Rho regulate actin cytoskeleton

• Leads to cytoskeletal changes

• Allows for cell movement

Extracellular Matrix and Signaling

• Macromolecules secreted by cells

  • Remain in the environment surrounding the cell

• Important in animal development

  • Can be permissive

  • Can be signaling

Extracellular Matrix is made of

• Integrins

• Proteoglycans

• Fibronectin

• Laminin

• Type IV collagen

• Matrix metalloproteases

Integrins

• Receptors for extracellular matrix macromolecules

• Also bind to molecules within the cell

• Can also provide signaling for transcription factors

  • May prevent apoptosis when bound to extracellular matrix

EMT

Epithelial-Mesenchymal Transitions

Changes in EMT

• Fewer cell adhesions

• Less cell-cell communication

• More motility

Where EMT is Seen

• Type I

  • Involved in implantation and gastrulation

  • Produces mesoderm and endoderm

  • Converted back to epithelial cells

• Type II

  • Involved in tissue healing and fibrosis

• Type III

  • Involved in cancer formation and metastasis

Cadherin Switch in EMT

• Regulated by several signal transduction pathways (TGF-b)

• E-cadherin gene transcription decreases, or protein cleaved by MMPs

Cadherin Switch

• Decrease in E-cadherin releases p120

• p120 works with actin controlling proteins, Rac, Rho, and cdc42

• Actin remodeled to form filopodia and lamellipodia

• Movement and invasion

• N-Cadherin binds to stromal cells

• Binds to FGFR– promotes cell survival, growth, migration

• Cleaved

  • Soluble N-cadherin can induce FGFR signaling in neighboring cells

  • Intracellular domain represses transcription

Changes in cell-cell junctions in EMT

• Adhesion junctions change

• Tight junctions and desmosomes decrease

Extracellular matrix changes in EMT

• increase in matrix metalloprotease (MMP) expression

• Destruction of some ECM components (invasion)

• Synthesis of some ECM components (movement)

Cell Death Pathways

• Apoptosis (programmed cell death)

  • Example: C. elegans 

  • Removes unnecessary structures, controls # of cells in tissues, sculpts complex organs

  • Different tissues = different signals

    • Some need signal to die

    • Some die without signal to live/grow

Extrinsic and Intrinsic Pathways

• Death signal

• Activates BAX and BAK

• Cytochrome c released from mitochondria

• Cytochrome c binds APAF-1

• Caspases activated