Chapter 3 - modified for details Flashcards
Three behaviours require cell-cell communication via the cell surface:
cell adhesion
cell migration
cell signalling.
Cell adhesion - Selective affinity
The surfaces of the cells have an affinity for certain other cells
Fx inner surface of ectoderm have positive affinity for mesodermal cells and negative for endoderm, causing mesoderm cells to adhere to the inside of the epidermis, but not endoderm cells. The cells (if mixed) are able to sort out into their proper embryonic positions.
Selective affinity changes during development, allowing cells to interact differently with other cell populations at specific times (extremely important for morphogenesis).
Cell adhesion - Differential adhesion hypothesis
Cells interact so as to form an aggregate with the smallest interfacial free energy => cells rearrange themselves into the most thermodynamically stable pattern.
The thermodynamic differences are caused by different types of adhesion molecules.
If A-A connections are stronger than A-B or B-B connections, sorting will occur, with A cells becoming central.
If A-A =/< A-B then mix, if A-A»_space; A-B then separate aggregates.
Cell adhesion - Cadherins
Calcium dependent adhesion molecules
Critical for establishing and maintaining intercellular connections
Crucial for spatial segregation of cell types and to the organization of the animal form.
TM molecules, interact with other cadherins on adjacent cells.
Can also serve as signalling molecules that change a cell’s gene expression.
Cell adhesion - Catenins
Catenins anchors cadherin inside the cell.
Protein complex, binds to actin (microfilament) cytoskeleton of cell.
Integrate epithelial cells into a mechanical unit and organizes cadherins, allowing them to form stable linkages
Cell migration is a common feature of both epithelial and mesenchymal cells, differences in how?
Involves a broad reorganization of the actin cytoskeleton.
- Epithelia – the motive force for migration is usually provided by the cells at the edge of the sheet, and the rest of the cells follow passively.
- Mesenchymal – individual cells become polarized and migrate through the extracellular milieu.
Cell migration - Stages of migration:
- Polarization
- Protrusion of leading edge
- Extracellular adhesion
- Release of adhesion
Cell migration - Stages of migration: Polarization
How a cell defines its front and its back
can be directed by diffusion signals (fx chemoattractant gradients)
or by signals from the extracellular matrix (reorganize the cytoskeleton so front and back become structurally different.)
Cell migration - Stages of migration: Protrusion of leading edge
polymerization of the actin microfilaments at the cell membrane, creating long parallel bundles (filopodia) / broad sheets (lamellipodia).
The actin becomes nucleated and connected to cadherins in the cell membrane.
Cell migration - Stages of migration: Extracellular adhesion
the moving cell, attaches to the surrounding matrix for something to push off on.
Key proteins are integrins (span cell membrane, connecting extracellular matrix to intracellular actin).
Myosin provides motive force along actin filaments.
Cell migration - Stages of migration: Release of adhesion
at rear of cell, allowing the cell to migrate in the forward direction.
It is probable that stretch-sensitive Ca2+-channels are opened and the released Ca2+ activates proteases that destroy the focal adhesion sites.
Cell signalling - Induction
Cells changing the behaviour of adjacent cells
Causing them to change shape, mitotic rate or cell fate
Close range interaction between two or more cells or tissues of different histories and properties.
Inducer often uses paracrine factors
Responder must have both the receptor for the inducing factor, but also the ability to respond to the signal (competence).
Often, one induction will give a tissue the competence to respond to another inducer.
Cell signalling - Reciprocal induction
Sometimes the inducer becomes the induced.
Two major modes of inductive interaction:
- Instructive interaction – a signal from the inducing cell is necessary for initiating new gene expression in the responding cell
- Permissive interaction – the responding tissue has already been specified and needs only an environment that allows the expression of these traits, fx extracellular matrix
Genetic specificity of induction is?
Tissue may be induced to induce certain genes, but can only comply with the instructions so far as its genome permits.
Organ-type specificity is controlled by inducing mesenchyme, species specificity is controlled by responding epithelium.
Paracrine factors: inducer molecules - Juxtacrine interactions
membrane proteins on one cell surface interact with receptor proteins on adjacent cell surfaces, the cell membranes are juxtaposed.
Paracrine factors: inducer molecules - Paracrine interaction
proteins synthesized by one cell diffuse over a small distance (ca. 15 cell diameters) to induce changes in neighbouring cells.
Paracrine factors: inducer molecules - Autocrine interaction
specific type of paracrine, the same cell secreting responds, not common fx seen on placental cytotrophoblast cells => explosive proliferation
Signal transduction cascades
End point of most paracrine factor pathways either involves regulation of TFs (alter gene expression) and/or regulation of the cytoskeleton (alter shape / migration).
One paracrine factor can have several end points. • RTK pathway • JAK-STAT pathway • Hedgehog pathway • Canonical Wnt pathway • Noncanonical Wnt pathways • SMAD pathway
Signal transduction cascades - RTK pathway
Paracrine factor receptors are often TM receptor tyrosine kinases (RTKs).
RTKs use ATP to phosphorylate specific tyrosine residues on particular proteins as the first step in the paracrine signalling cascade.
Each RTK can bind only one type of ligand (or one small set).
Signal transduction cascades - JAK-STAT pathway
Extremely important in differentiation of blood cells, the growth of limbs and the activation of the casein gene during milk production.
Signal transduction cascades - Canonical Wnt pathway
Used for sending signals to nucleus and change gene transcription
Signal transduction cascades - Non-canonical Wnt pathway
Wnt proteins use these to affect calcium transport into cells as well as altering the actin and microtubule cytoskeleton.
Signal transduction cascades - SMAD pathway
Results in gene transcription or repression
Extracellular matrix as a source of developmental signals
Insoluble network consisting of macromolecules secreted by cells into their immediate environment
Critical region for much of animal development
Made up of the matrix protein collagen, proteoglycans and a variety of specialized glycoprotein molecules such as fibronectin and laminin.
Cell migration, cell adhesion and formation of epithelial sheets + tubes depend on the ability of cells to form attachments to extracellular matrices.
Not passive, can promote diffusion, retard diffusion or degrade paracrine factors.
Proteoglycans play critically important roles
In the delivery of paracrine factors, by binding them and presenting them in a high concentration to their Rs.
Block of synthesis blocks normal cell migration, morphogenesis and differentiation.
Glycoproteins are responsible for organizing the matrix and the cells into an ordered structure. Name two most important and general function.
- Fibronectin – general adhesive
* Laminin – one of the major components of basal lamina
Integrins
Family of R complexes
Spans the cell membrane, integrating extracellular and intracellular scaffolds, allowing them to work together.
Movement through contracting actin filaments against fixed extracellular matrix.
Integrins can signal from the outside of the cell to the inside, altering gene expression.
Bound integrin prevents the activation of genes that promote apoptosis.
Binding of integrins to an extracellular matrix can stimulate the RTK pathway.
Anoikis
“death-upon-detachment”
when focal adhesions linking an epithelial cell to its extracellular matrix are broken, the caspase-dependent apoptosis pathway is activated and the cell dies (major weapon against cancer).
Epithelial-Mesenchymal transition
A polarized, stationary epithelial cell, which normally interacts with basal lamina through its basal surface, becomes a migratory mesenchymal cell that can invade tissues and form organs in new places.
EMT also important in adults, needed for wound healing, and unfortunately used in cancer metastasis
5 types of cadherins:
- E-cadherin – expressed on all early mammalian embryonic cells, later restricted to epithelial tissues
- P-cadherin – predominantly on placenta, helps it stick to the uterus
- N-cadherin – highly expressed on cells of the developing central nervous system, may mediate neural signals
- R-cadherin – critical in retina formation
- Protocadherins – lack the attachment to the actin skeleton through catenin. Expression of similar keeps migrating epithelial cells together, dissimilar is an important way to separate tissues.
Differences in cell surface tension and tendency of cells to bind together depends on strength of cadherin interactions, achieved through: (2)
- Quantitatively – more cadherins on opposing surfaces = tighter adhesion
- Qualitatively – some binds to different types, some don’t
What is focal adhesion?
The point of connection between actin and integrin on cell membrane where it contacts the extracellular matrix.
Does a structure/organ need to be fully differentiated to have a function?
Before a tissue has its “adult” functions, it can have critically important transient functions in building the organs of the embryo.
What is a cilia?
Extensions of the cell membrane made by microtubules
EMT done how?
Usually initiated by paracrine factors from neighbouring cells, instructing the target cells to:
• Downregulate cadherins
• Release attachment to laminin + other basal components
• Rearrange their actin cytoskeleton
• Secrete new extracellular matrix molecules characteristic of mesenchymal cells
The induction of numerous organs is effected by a relatively small set of paracrine factors, grouped based on structure:
- The fibroblast growth factor (FGF) family - Functions through RTK and JAK-STAT pathways.
- The Hedgehog family - Works through Hedgehog pathway.
- The Wnt family
- The TGF-beta superfamily
- Some paracrine factor proteins have no or few close relatives and can’t be grouped but still have important roles during development. Fx epidermal growth factor, hepatocyte growth factor, neurotrophins and stem cell factor.
Paracrine factors - The Wnt family
Family of cysteine rich glycoproteins
Critical in:
- Formation of fly wings
- Establishing the polarity of insect and vertebrate limbs
- Promoting the proliferation of stem cells
- Several steps of the mammalian urogenital system development
Uses conventional or nonconventional Wnt pathway.
Paracrine factors - The TGF-beta superfamily
TGF = transforming growth factor
Regulates some of the most important interactions in development.
(fx formation of extracellular matrix, cell division, migration and differentiation, bone formation, apoptosis, specifying left and right sides of vertebrate body axis and the different regions of the mesoderm).
Includes:
TGF-beta family
Nodal and activin families
bone morphogenetic proteins (BMPs)
Uses SMAD pathway.
Signal transduction cascades - Hedgehog pathway
Extremely important in vertebrate limb development, neural differentiation and facial morphogenesis.
Often used by embryo to induce particular cell types and to create boundaries between tissues.
Notch proteins:
Binds to a family of ligands (Delta, Jagged or Serrate proteins)
Uses Notch pathway.
Involved in the formation of numerous vertebrate organs (kidney, pancreas, heart, eye)
Extremely important Rs in the nervous system (binding of Notch to Delta = do not become neuron).
Juxtacrine signalling, two of the most widely used families of juxtacrine factors:
- Notch proteins
* Eph receptors
Eph Rs
Ligand = ephrin
Binding of ligand and R gives rise to signal in both cells involved. Often attraction or repulsion signals.
Ephrins are often seen where cells are told where to migrate or where boundaries are forming, fx in formation of blood vessels and neurons.
Signal transduction cascades - RTK pathway
Paracrine factor receptors are often TM receptor tyrosine kinases (RTKs).
RTKs use ATP to phosphorylate specific tyrosine residues on particular proteins as the first step in the paracrine signalling cascade.
Each RTK can bind only one type of ligand (or one small set).
