Biology Reference
In-Depth Information
laying down thick contractile actin cables parallel to the direction of the tension.
20
There is
evidence from a number of systems that this response is mediated by local activation of
Rho.
21
Contractile actin cables have two effects: they provide the cell with a means to resist
being stretched by tensile forces, and they also block the formation of lamellipodial structures
on the newly free edge of the cell, just as stress fibres at the lateral margins of a migrating
fibroblast antagonize the production of a lamellopidium there (Chapter 8). Because tension
is always greatest parallel to the local wound edge, actin cables are automatically positioned
in the right place. The contractile actin cable can function only if it is connected by adherens
junctions to the cable in adjacent cells. If adhesion at these junctions is inhibited using a func-
tion-blocking anti-E-cadherin antibody, actin filaments disappear and the free edge of the cell
makes a lamellopodium instead.
22
The lamellipodium crawls forward and healing still takes
place by a secondary migratory mechanism that has been selected automatically and quite
directly by the failure of the principal, actin-cable-based system.
When the actin cables are being assembled, it is clearly important that a substantial supply
of E-cadherin is made available in precisely the correct place to connect the new actin cables
of adjacent cells. This supply is assisted by the dependence of adherens junction stability on
actin filaments. If the actin of cultured cells is removed by cytochalasin, junction components
are internalized for re-use.
23
Thus reorganization of actin to a tense band at the wound edge
automatically assists reorganization of junctions, and well-organized junctions assist the
stability of the actin that terminates in them. At least part of this mechanism probably rests
on the fact that binding of the extracellular domain of E-cadherin to E-cadherin on adjacent
cells allows its intracellular domain to recruit the actin nucleating molecule, Arp2/3.
24
Adja-
cent cells therefore adjust their arrangements of actin and junctions continuously and itera-
tively, and since all cells connect to neighbours on both sides, the actin band is always
arranged appropriately at the tissue scale by events at the molecular scale. As the hole finally
zips up, in a manner similar to that described for D. melanogaster, new adhesions that form
between cells of opposing sides encourage actin filaments to end in them, where tension is
now concentrated, and the thick band that was at the wound edge disintegrates to give
rise to a 'normal' ring of cortical actin filaments running inside the adherens junctions around
the cell.
It is interesting to observe that the healing of wounds in embryonic epithelium uses mech-
anisms very similar to the healing of wounds in the membrane of a single cell. The zone
immediately underneath the plasma membrane of most cells is richly supplied with actin
fibres. If a plasma membrane is breached, for example, with a fine needle, external Ca
2
þ
ions flood in to it and trigger a healing response.
25
The Ca
2
þ
causes an almost immediate
fusion of the membranes of cytoplasmic vesicles to form a vesicle membrane bilayer that
plugs the damaged site. This action plugs the hole, but does not reinstate the normal plasma
membrane or the normal cell cortex underneath it. To reinstate the proper sub-membrane
environment, the undamaged cell cortex from around the hole moves inwards radially until
it has completely filled in the damaged site. Within 30 seconds or so of wounding, a cable of
actin and myosin forms around the circumference of the hole and that cable contracts, pinch-
ing off the hole and dragging the normal cell cortex with it.
26
Yet again, activity of Rho
GTPase is essential for the formation of this healing contractile ring.
26
A similar contractile
ring of actin is formed during normal cytokinesis. It is therefore possible that this key means
to close over a hole was invented just once in evolution, probably for cytokinesis, then
