Biology Reference
In-Depth Information
the developing long-bones. As condensation proceeds, expression of Cadherin 2 rises mark-
edly in the condensing cells.
4
Limb mesenchyme can be removed and cultured in small
clumps ('micromass culture') and condensation will occur within these clumps as it does
within an intact limb.
5
Treating cultured mesenchymes with function-blocking anti-Cadherin
2 inhibits condensation
4,6
and expressing dominant negative mutants of Cadherin 2 has
the same effect
in vivo.
7
These observations strongly suggest that condensation is driven
by Cadherin 2-mediated cell-cell adhesion.
The appearance of Cadherin 2 on some of the mesenchyme cells has the effect not only of
sticking them together, but also of sorting them out from cells not expressing the molecule.
Mixtures of cells that express different amounts of cadherin have an inherent ability to
sort out so that those expressing more cadherin cluster together in the inside. The ability
of Cadherin 2, and of its close relative Cadherin 3, to mediate this sorting has been tested
by mixing cells that express high levels of cadherin with those that express lower levels of
the same cadherin; the cells sort out spontaneously so that the high-expressers aggregate
inside the low-expressers (
Figure 14.1
).
8,9
That different levels of cadherin expression can
cause cells to sort is therefore in no doubt, but the precise mechanism that achieves this is
not yet clear and two rival theories have been proposed.
The first theory, sometimes called the 'differential adhesion hypothesis' or the 'Steinberg
hypothesis' after its first champion,
10,11
is based on simple physics and involves no 'biolog-
ical' features beyond the requirement that cells move about. According to the Steinberg
hypothesis, sorting is driven by the second law of thermodynamics. This law describes
the tendency of systems that are capable of rearrangement to reach a state of minimum
free energy. The free energy of the binding domains of an adhesion molecule is minimized
when it is adhering to its ligand (if that were not true, it would not be an 'adhesion' mole-
cule). The free energy of a cell expressing a homophilic adhesion molecule is therefore mini-
mized when it is completely surrounded by other cells that express the same molecule.
A mixture, of cells that express the adhesion molecule and similar cells that do not, would
therefore be expected to sort out so that adhesive cells amass in the middle, where the
number completely surrounded would be maximized. Less adhesive cells would be left
on the outside (
Figure 14.2
). The explanation is broadly similar to that which accounts
for the separation of immiscible liquids. Computer simulations of cell sorting by the Stein-
berg method have been constructed and they result in sorting that has an appearance
remarkably similar to that seen in mixtures of real cells, although sorting can be surpris-
ingly slow.
12
The pure differential adhesion hypothesis did, however, run into considerable
FIGURE 14.1
Spontaneous sorting of cells expressing high and low levels of N- (or P-) cadherin.
