Biology Reference
In-Depth Information
increased too much compared with proliferation, branching is lost and the tip just swells up
as it does when inhibitors of ROCK are used to weaken cell-cell adhesion and stress fibres.
80
Whereas, if motility is decreased too much, the surface of the tip becomes corrugated with too
many small protrusions, as it does when PTEN, part of the chemotaxis system that acts
downstream of GDNF, is inhibited.
81
In principle, any negative feedback between the production of chemoattractants by cells and
the arrival of branches in their vicinity could be used to organize the branching tree. For
example, low oxygen conditions induce cells to produce the ramogenic chemoattractant of
endothelia, VEGF.
82
e
84
The VEGF induces sprouting of capillaries and attracts them,
85,86
and
once blood flow through the new capillaries is established, the concentration of available
oxygen rises, VEGF synthesis falls, and sprouting ceases. Thus the extent and direction of
branching is determined by local need, and the branching system organizes itself accordingly.
Similar feedback systems can be found in control of epithelial branching. In the kidney, for
example, 'virgin' mesenchyme that has not yet been invaded by the branching ureteric bud
produces GDNF,
87
which encourages branching andprobably sets its direction too. The ureteric
bud is a source of short-range signals that cause the differentiation of mesenchyme once it
reaches it; the differentiation process is complex, because it gives rise to epithelial nephrons.
88
However, from the point of view of branching, what is important is that the differentiating
mesenchyme ceases to produce GDNF. It is therefore no longer attractive to the ureteric bud.
Indeed, after a delay of some hours, the mesenchyme produces negative regulators of branch-
ing, such as TGF
and BMP2 that signal via the Smad pathway.
89
It is reasonable to assume that
this pattern of protein expression ensures that the ureteric bud is attracted to areas that it has not
yet penetrated and not encouraged to branch into areas it already served (
Figure 20.12
).
b
FIGURE 20.12
Feedback systems in the developing kidney cause areas of virgin mesenchyme to be attractive to
ureteric bud branches, because they produce factors such as GDNF, and areas already penetrated to cease to be
attractive or to induce branching.
