Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

1152 Chapter 21: Development of Multicellular Organisms
Figure 21–10 Genesis of asymmetry through lateral inhibition and
positive feedback. In this example, two cells interact, each producing
a substance X that acts on the other cell to inhibit its production of X, an
effect known as lateral inhibition. An increase of X in one of the cells leads
to a positive feedback that tends to increase X in that cell still further, while
decreasing X in its neighbor. This can create a runaway instability, making
the two cells become radically different. Ultimately, the system comes to rest
in one or the other of two opposite stable states. The final choice of state
represents a form of memory: the small influence that initially directed the
choice is no longer required to maintain it.
cell 1 cell 2
X
X X
X
X X
X
X
transient bias creates
slight asymmetry
what if there is no clear initial asymmetry? Can a regular pattern arise spontaneously
within a set of cells that are initially all alike?
The answer is yes. The fundamental principle underlying such de novo pattern
formation is positive feedback: cells can exchange signals in such a way that
any small initial discrepancy between cells at different sites becomes self-amplifying,
driving the cells toward different fates. This is most clearly illustrated in the
phenomenon of lateral inhibition, a form of cell–cell interaction that forces close
neighbors to become different and thereby generates fine-grained patterns of different
cell types.
Consider a pair of adjacent cells that start off in a similar state. Each of these
cells can both produce and respond to a certain signal molecule X, with the added
rule that the stronger the signal a cell receives, the weaker the signal it generates
(Figure 21–10). If one cell produces more X, the other is forced to produce
less. This gives rise to a positive feedback loop that tends to amplify any initial
difference between the two adjacent cells. Such a difference may arise from a
bias imposed by some present or past external factor, or it may simply originate
from spontaneous random fluctuations, or “noise”—an inevitable feature of the
genetic control circuitry in cells (discussed in Chapter 7). In either case, lateral
inhibition means that if cell 1 makes a little more of X, it will thereby cause cell 2 to
make less; and because cell 2 makes less X, it delivers less inhibition to cell 1 and
so allows the production of X in cell 1 to rise higher still; and so on, until a steady
state is reached where cell 1 produces a lot of X and cell 2 produces very little. In
the standard case, the signal molecule X acts in the receiving cell by regulating
gene transcription, and the result is that the two cells are driven along different
pathways of differentiation.
In almost all tissues, a balanced mixture of different cell types is required.
Lateral inhibition provides a common way to generate the mixture. As we
shall see, lateral inhibition is very often mediated by exchange of signals at cell–
cell contacts via the Notch signaling pathway, driving cell diversification by
enabling individual cells that express one set of genes to direct their immediate
neighbors to express a different set, in exactly the way we have described (see also
Figure 15–58).
X
X X
X X
X
X X
X X
X X X
X X
X X
X
X
X
POSITIVE FEEDBACK:
asymmetry is self-amplifying
X
MBoC6 m22.12/22.10
Short-Range Activation and Long-Range Inhibition Can Generate
Complex Cellular Patterns
Lateral inhibition mediated by the Notch pathway is not the only example of pattern
generation through positive feedback: there are other ways in which, through
the same basic principle, a system that starts off homogeneous and symmetrical
can pattern itself spontaneously, even in the absence of an external morphogen.
Positive feedback processes mediated by diffusible signal molecules can operate
over broad arrays of cells to create many types of spatial patterns. Mechanisms of
this sort are called reaction-diffusion systems. For example, a substance A (a shortrange
activator) may stimulate its own production in the cells that contain it and
in their immediate neighbors, while also causing these cells to produce a signal
I (a long-range inhibitor) that diffuses widely and inhibits the production of A in
cells farther away. If the cells all start the same, but one group gains a slight advantage
by making a little more A than the rest, the asymmetry can be self-amplifying