Cell adhesion, migration and motility Flashcards
What does failure of cells to migrate cause?
Cell, tissue and organism dysfunction and death
What are the roles of adhesion in development?
1) Sperm to oocyte - to transfer paternal DNA
2) Cells begin to express E-cadheirn (adhesion molecules) –> compaction
3) Differences in adhesion cause cells to divide into 2 groups: Inner cell mass (give rise to embyro) and trophoblast (extra-embryonic)
4) Cell implantation into the cellular wall
What is adhesion needed in neural tissue?
- Loss of adhesion from the dorsal nerual tube to form neural crest cells
- Neural crest cells migrate, so must slightly adhere to substrate (but not too much)
- Neural crest cels aggregate once finished migrating - changing adhesion properties again
What did studies on sponges by Wilson show?
- When the cells are deaggregated, they are still able to reaggregate and reorganise into separate tissues based upon their adhesion
- See regionalisation of tissues
What are L cells?
Cells that do not aggregate (don’t express cadherins)
What can L cells be used for?
How?
To study cadherins:
- Transfect L cells with transgenes that express different cadherins and monitor their behaviour
How cant the L cells organise when transfected with cadherins?
Into different groups with the properties of:
1) Different cadherins
2) Different levels of the cadherin
How do cadherins interact?
Bind homophillically to the same cadherin with the extracellular N terminus
Where does Ca2+ bind to cadherins and what does this cause?
Binds at the hinge region to stabilise the cadherin and allow it to interact (cant interact when no Ca2+ is bound - floppy)
How can cells modulate levels of interaction and adhesion? (2 ways)
1) By the type of cadherin they express
2) By the levels of Ca2+ released into the extracellular environment
How are cadherins organised in the cell?
In arrays:
- In the same cell, interact with partners to form lines
- On neighbouring cells - they are arranged perpendicular
- Highly organised: can be adherent on one side of the cell but not the other
What are the 2 types of cadherins?
1) Classical
2) Non-classical
How many different types of cadherins are there in vertebrates?
Over 100
Where are classical cadherins expressed?
In adherens junctions (holds cells together)
What is the structure of classical cadheirns?
- Single pass transmembrane domain
- Repeated domains
- Extracellular hinges
- N terminus extracellular
What are examples of classical cadherins?
1) E-cadherin (epithelial)
2) N-cadherin (neural)
What is the first cadherin to be expressed in the embryo?
What is this cadherin important for?
E-cadherin
Also important for multicellular function
Where is N-cadherin expressed?
In the neural tube and other tissues
What are non-classical cadherins used for?
Specialised for unique functions
How are non-classical cadherins different to classical cadherins?
- Contain many different domains that mediate other protein-protein interactions
- Can have many transmembrane domains
How are non-classical cadherins similar to classical cadherins?
Still have homology in their domains
What is an important types of non-classical cadherin and where is it present?
Protocadherins in the nervous system
What is the structure of protocadherins?
Has many different isoforms which have occurred through alternative splicing of a single gene
What 2 things are protocadherins involved with?
1) Specifying synapses in the brain - confer complex connectivity
2) Involved in self-avoidance behaviour
Why is the expression of cadherins complex?
- Can have strict boundaries
- Can have graded expression
- Can have overlapping expression of cadherins
What are catenins and where do they bind?
What are their functions?
INTRACELLULAR proteins
Bind to the intracellular portion of cadherins to link them to actin in the cytoskeleton
What are the 2 roles of catenins?
1) Structural role - when bound to cadherin and actin
2) Signalling role
How do catenins have a signalling role?
When bound to cadherin, beta catenin can control the proliferation of the cell through c-myc
How are junctions stabillised when cadherin interacts with the neighbouring cell?
- Interaction forms tension on the cadherin
- This stretched out the alpha catenin from a folded state to an unfolded state (physical confirmational change of catenin)
- This confirmational change reveals a binding site for vinculin
- Vinculin binds to alpha catenin and to other actin filaments to reinforce, stabilise and strenghten the junction (cross-linking)
- Once stabilised, this interaction can give rise to an entire change within the cell (myosin is attached to actin)
What does Rho do when activated?
Leads to strong actin filaments forming
What activates Rho?
Beta-catenin mediated junction formation
What happens to actin in a relaxed state?
Disorganised threads of actin
What does constitutively active Rho lead to?
Stress fibre formation
Describe the cadherins in the early embryo
1) E-cadherin expressed in the very early embryo
- In the epithelium
2) Newly formed mesoderm lose E-cadherin expression
- Able to dissociate and move inside the embryo
3) Neural tube upregulates N-cadherin to replace the E-cadherin
- Allows the neural tube to form
Why is E-cadherin expressed in the very early embryo?
To pull cells together in the compacting stage
What cadherin does the roof plate and floor plate express?
Cadherin 6B
What cadherin do the neural crest cells express?
Cadherin 7
Where are selectins expressed?
On the cell surface
How many transmembrane domains do selectins have?
1
What do selectins depend upon?
Ca2+
What do selectins bind?
Carbohydrates on neighbouring cells that are expressed specifically on certain cells
What are the roles of selectins?
In the immune system and neutrophil trapping
What is the structure of P-selectin?
- Repeated sequences with different domains at the top
- Intracellular domain linked to actin through anchor proteins
What are the domains at the top of P-selectin?
- Lectin domain
- EGF-like domain
When and where is P-selectin induced?
During inflammation (tissue damage of infection)
In the endothelial cells
What happens in the blood vessel upon infection?
Neutrophils have to leave the blood vessel - invade the tissue:
1) Neutrophils become adherent to the outside of the blood vessel wall - have a rolling behaviour
2) Once cells stop rolling - leave blood vessels and move between the endothelial cells
What is the rolling behaviour of the neutrophills mediated by?
Selectins that are up-regulated during inflammation
Roll due to blood flow
What is the movement of neutrophills into the endothelial cells mediated by?
Integrins
What are the 2 different types of Ca2+ independant cams?
1) Secreted and part of the ECM
2) Have a transmembrane domain, intracellular domain and numerous repeats
What are the kinds of repeats that Ca2+ independant cams can have?
- Ig repeats
- Fibronectin type III domains
How many different types of Ca2+ independant cams are there?
What are the main types?
Many different types
Main types: neural cell adhesion molecules (N-CAMs)
How do Ca2+ independant cams arise?
From alternative splicing of a single gene to give rise to many different isoforms
What binding do Ca2+ independant cams mediate?
Homophillic binding
What confers the diversity of Ca2+ independant cams?
Highly glycosylated post-translationally
What interactions do Ca2+ independant cams mediate?
Interactions between the ECM
Interactions between different cells
Along with glycosylation, what is the other modification that occurs to Ca2+?
Have a SPECIFIC, VARIABLE polysialic acid modification
What is the difference between immature cells and mature cells in the neural tube?
Immature:
- Higher levels polysialic acid
- Less adhesion
- Can move around more
Mature:
- Less polysialic acid
