Lecture 16. Cell Motility and Chemotaxis Flashcards
What does Dictyostellium discoideum (amoeba) do in response to cAMP?
Aggregates
What is chemotaxis?
The ability to sense and move towards or away from a directional signal
What functions of the body rely on chemotaxis?
Directed cell movements during development (e.g. gastrulation, neural crest migration and primordial germ cell migration)
Immune surveillance (phagocytosis of pathogens)
The inflammatory response to injury (lymphocyte migration)
Wound healing (fibroblast migration)
How can a neutrophil successfully chase down and phagocytose a bacterium as a part of immune surveillance?
The bacteria secretes a tri-peptide which is sensed by receptors on the neutrophil plasma membrane
How can lymphocytes rapidly migrate in response to injury?
Piercing a zebrafish larvae can visualise the process (larva is optically transparent)
Lymphocytes can be seen migrating to the site of injury. At later times, Fibroblasts which initially appear static will migrate to the wound site to repair the wounded area
How is the lamellipod extended by actin filament assembly and disassembly at the leading edge?
Requires actin (particularly branching actin) polymerisation regulated by the Arp2/3 complex which sits on the side of a filament in order to nucleate new actin filament formation
As this actin is polymerised, it pushes the plasma membrane forward int eh direction of the chemotaxic agent after receiving a signal from the extracellular surface through a transmembrane receptor
What actin structures make up the lamellipodia?
Branched networks that help push the cell forward
How does a particular cell move forward during chemotaxis?
- Locomotion begins with the extension of one or more Lamellipodia from the leading edge of the cell. This involves branched actin polymerisation which pushes the membrane forward
2) New focal adhesions (feet) are formed at specialised sites on the plasma-membrane. These contain Integrins which link actin to the extracellular matrix (ECM)
3) The bulk of the cytoplasm is pushed forward by contraction of Actin-Myosin II bundles (stress fibers) at the rear of the cell in a process called translocation
4) The trailing edge of the cell detaches from the ECM and retracts into the cell body. During this process the endocytic machinery internalises integrins and transports them to the front of the cell to be used again (endocytic recycling)
What actin structures make up the filopodium?
Tight parallel bundles
What actin structures make up the stress fibres near the back end of the cell?
Contractile bundles that have to be far enough apart to allow myosin motor proteins to enter, allowing for contraction
What regulates the actin assembly?
The Rho superfamily of GTPases
Microinjection of dominant activated forms of the Cdc42, Rac and Rho (members of the Rho superfamily of GTPases) have different effects on actin filament organisation in cells
What role does Rho have in the formation of stress fibres?
Rho activates formin which makes straight actin filament cables which are then bundles together to create contractile acting bundles
Rho kinase stimulates the movement of a myosin motor protein
What role does Rac have in the formation of the lamellipodia?
Rac activates WASp which activates ARP2/3 complex which activates actin polymerisation, activating lamellipodia formation
What role does Cdc42 have in the formation of the filopodia?
Cdc42 activates the formin which causes actin polymerisation that creates the filopodia (no myosin activity required)
How is the intracellular distribution of each class of GTPase controlled furing chemotaxis?
Each class of GTPase is controlled so that a gradient is formed within the cell. At the leading (growing) edge Cdc42 activation promotes formin and Arp2/Arp3 dependent actin assembly to promote filopodia and lamellapodia growth.
This in turn stimulates Rac GTPase which further promotes branched actin network assembly behind the leading edge. Rac activation leads to Rho GTPase activation at the lagging edge of the cell which promotes stress fibre formation and myosin II activation which powers forward movement of the bulk of the cell contents. This systems is highly dynamic as the cell can rapidly change direction in response to changes in concentration and direction of chemotactic signals.