M.r. capecchi, Science 301:363–367, 2003.) earlier, lateral inhibition mediated by Notch signaling is crucial for both cell diversification and fine-grained patterning in an enormous variety of tissues in all animals.
One example is the development of sensory bristles in Drosophila, most easily seen on the fly’s back, but also present on most of its other exposed surfaces. Each of these is a miniature sense organ, consisting of a sensory neuron and a small set of supporting cells. Some bristles respond to chemical stimuli, others to mechanical stimuli, but they are all constructed in a similar way (Figure 21–34). The pro-neural genes Achaete and Scute mentioned earlier mark the patches of epidermis within which bristles will form. Mutations that eliminate the expression of these genes at some of their usual sites block development of bristles at just those sites, and mutations that cause expression in abnormal sites cause bristles to develop there.
The initial cells expressing the proneural genes are called proneural cells, and they are primed to take the neurosensory pathway of differentiation, but which of the cells will actually do so depends on competitive interactions among them. In the first round of these interactions, a single cell within each small group of proneural cells is picked to serve as the progenitor of the bristle. This single cell is called the sensory mother cell. It becomes distinct from the other cells of the cluster through lateral inhibition mediated by the Notch signaling pathway. This operates in the way we discussed earlier. The cells in the proneural cluster initially all express both the transmembrane receptor Notch and its transmembrane ligand Delta, along with proteins that regulate the signaling activity of Delta. Wherever Delta activates Notch, an inhibitory signal is transmitted that diminishes the tendency of the Notch-activated cell to specialize as a sensory mother cell.At first, all the cells in the cluster inhibit one another. However, receipt of the signal in a given cell diminishes that cell’s ability to fight back by delivering the inhibitory Delta signal in return. This creates a competitive situation, from which a single cell in each cluster—the future sensory mother cell—eventually emerges as winner, sending a strong inhibitory signal to its immediate neighbors but receiving no such signal in return (Figure 21–35). If a cell that would normally become a sensory mother cell is genetically disabled from doing so, a neighboring proneural cell, freed from lateral inhibition, will become a sensory mother cell instead.
The sensory mother cell goes through a short program of further divisions to generate the set of cells that form the final bristle. Notch signaling acts repeatedly at successive stages in this program to drive the descendants of the sensory mother cell along different pathways and assign them to their various specialized fates. However, it does so in conjunction with additional mechanisms that bias the outcome of the competition mediated by lateral inhibition. Determinants that
Figure 21–34 The basic structure of a mechanosensory bristle. the lineage of the four cells of the bristle—all descendants of a single sensory mother cell—is shown on the left. the sensory mother cell, once it is specified, generates this set of cells through a short program of division cycles. In each generation of the progeny, lateral inhibition operates again to drive the newborn cells toward different fates: one of the ultimate progeny will become the neuron; another, the shaft of the bristle; others, supporting cells of various sorts. as the sensory mother cell and its progeny divide, certain proteins are allocated preferentially to one of each pair of newborn sister cells, biasing the outcome of the lateral-inhibition competition mediated by Notch signaling.
are asymmetrically localized inside the dividing cells have this role in sensory bristle development. They are also important in other contexts, as we now discuss.