Biology Reference
In-Depth Information
about the planar (cell) polarity (or PCP) pathway. This has had two unfortunate effects. One is
that the use of these molecules, some of which are involved in aspects of Wnt signalling, in
any system is now referred to as use of the PCP pathway, even where there is no a priori
reason to suppose that the signalling is involved in direction-finding in that system. The
second is that reviewers of papers have become resistant to anybody using the phrase 'planar
polarity' where there is no proven involvement of that specific molecular pathway, even
where the phenomenon of polarity within a plane demonstrably exists. This is just one of
many examples of molecular biologists claiming a higher-level term for a more limited
use, and in so doing losing the original and useful meaning.
)
Planar polarity can be likened to cells having an internal compass, which defines one side of
them as 'North' and which can respond to the orientations of neighbouring cells' compasses
(
Figure 16.7
). The polarization of epithelial cells so that one side is different to the others is remi-
niscent, in broad principle, to the polarization of migrating cells so that only one side will make
a lamellipodium (Chapter 9). Polarization of the migrating cells of D. discoideum
d
the example
considered in most detail in Chapter 9
d
rested on a combination of short-range positive feed-
back loops, by which each part of the cell tended to maintain its own character, and long-range
inhibitory feedback loops by which the 'opposite' character was prevented from invading. The
same basic pattern of feedback loops seems to be responsible for maintaining planar polarity
within epithelial cells, although the molecular details are very different.
On one side of the cell (North in terms of the compass analogy in
Figure 16.7
) there are
complexes containing the transmembrane cadherin-type cell adhesion molecule Flamingo
(Fmi: called 'Starry night' in vertebrates), the transmembrane signalling molecule Frizzled
(Fz), the cytoplasmic proteins Dishevelled (Dsh: called 'Dvl' in vertebrates) and Diego (Dgo).
On the other (South) side of the cell are complexes containing the same homophilic adhesion
molecule Flamingo, the transmembrane protein Strabismus (Stbm: called 'Vangl' in verte-
brates), which can bind to Flamingo andmediate adhesion, and the cytoplasmic protein Prickle
(Pk:
Figure 16.8
). It is clear that the two sets of complexes aremutually antagonistic. Not all of the
details of this antagonism are understood but at least the broad details have become reasonably
clear. Frizzled can be phosphorylated; when it is in its most strongly phosphorylated state, it
remains stable on the plasma membrane, whereas when it is dephosphorylated it can be inter-
nalized by endocytosis. This internalization is important to the ability of Frizzled to trigger sig-
nalling pathways that control cytoskeletal behaviour (see below).
11,12
Dishevelled increases the
phosphorylation of Frizzled, stabilizing it on the membrane (indeed, when strongly activated,
Dishevelled can phosphorylate Frizzled somuch that it reduces its ability to be internalized and
to signal; since Dishevelled is itself activated by Frizzled, this constitutes a negative feedback
loop to keep the rate of signalling by Frizzled within reasonable limits).
13
At the Northern
end of the cell, the presence of Frizzled on the membrane and the presence of Dishevelled in
the underlying cytoplasmis therefore self-reinforcing. Strabismus promotes dephosphorylation
of Frizzled (possibly by competing for Dishevelled),
13
and therefore leads to Frizzled being
internalized and lost from themembrane. In addition, Prickled (whichmay be activated by Stra-
bismus) inhibits the action of Dishevelled. At the Southern end of the cell, the presence of Stra-
bismus and Prickled correlates with the absence of Frizzled.
14
)
One of the most famous examples is 'mutant', which originally had a meaning much more general than an
alteration in the sequence of base pairs in DNA.
