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.
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).
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 short-range 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
POSITIVE FEEDBACK: asymmetry is self-amplifying