Biology Reference
In-Depth Information
concentration will be highest where concave surfaces make many TGF
-producing cells face
a small volume of gel and lowest where convex curvature makes cells face a large volume of
gel). This effect on concentration may be a plausible mechanism in a gel but is unlikely in
bulk medium subject to convection currents, as in the island system described in
Figure 20.4
.
Further experiments from the Nelson group
15
focused on ScP2 mouse mammary epithelial
cells, which can undergo a TGF
b
-induced epithelium-to-mesenchyme transition so complete
that even smooth muscle actin begins to be expressed; one of the features of this transition is
greatly enhanced motility. The probability of these cells undergoing epithelium-to-mesen-
chyme transition in response to modest concentrations of TGF
b
is increased markedly by
curvature in two-dimensional, gel-free cultures. What is more, this effect depends on stress
fibres organized by ROCK and on E-cadherin-mediated cell-cell adhesion, both of which are
concerned with the transmission of mechanical tension.
The picture obtained from the MDCK and mammary cell models is therefore one in which
new branches arise by enhanced cell motility and changing tissue geometry feeds back to
control the probability of advance, making smooth edges unstable and favouring the forma-
tion of branches and branches of branches. How well does this picture reflect branching
systems
in vivo
?
The embryonic branching tissue that is most similar to the MDCK model, at least of those
that have been studied closely, is the tracheal system of
Drosophila melanogaster
. This tissue,
which has already been described to some extent in Chapter 19, is unusual because it
contains very few cells, and its sprouting and advance tends to be led by the activity of clearly
identifiable individual cells. In these respects, it is morphologically similar to the MDCK cell
system and distinct from most mammalian epithelia, which tend to feature the collective
actions of tens of cells rather than a few individual pioneers. That is not to say that tracheae
are simple; even though they consist of fewer than 100 cells even when mature, they include
different zones with different patterns of cell arrangement. In the main 'trunks', two to five
cells surround the lumen. In the principal branches, the tubes are narrower and are sur-
rounded by a single cell that has curved around to make a seamed tubule by making junc-
tions with itself. The finest tubes are hollow processes from a single cell (
Figure 20.5
).
There are also tubes formed by fusion between adjacent tracheal systems; these have already
been described in Chapter 19.
The tracheal system of each body segment forms from an invagination of about 80 cells
from body wall. Unlike MDCK cells, and unlike almost every vertebrate branching system,
these cells complete their morphogenesis without any further cell division. This may be an
adaptation to the very fast development of
D. melanogaster
, which allows a mere 12 hours
for the tracheal system to be completed. Sprouting of branches is driven not by HGF but
by the protein Branchless,
16
a homologue of mammalian FGF: Branchless signals via the
FGF receptor homologue Breathless
17
(both proteins are named after the phenotype caused
by their mutation: absence of a proper tracheal system). Once they receive the Branchless
signal, some cells in the invaginations produce spikes called 'cytonemes' that carry the
Breathless receptors and are used for chemotactic guidance,
18,19
and become the leading
cells of sprouting branches.
20
These cells show strongly activated MAP-kinase.
21,22
No infor-
mation is yet available on activation of PI-3-kinase or Stat3 pathways, but it is known that
the downstream effector, Akt, is involved.
23,24
b
It is also known that formation of tracheal
filopodia is under the control of cdc42.
25
