Developmental events unfold over minutes, hours, days, weeks, months, or even years, with each organism following its own strict timetable. The cascades of inductive interactions and transcriptional regulatory events described earlier take time, as signals are transmitted and transcription regulators are synthesized and then bind to DNA to activate or repress their target genes. At the beginning of this chapter, we compared development with an orchestral performance. There are many players, and each must do the right thing at the right time; yet there is no leader or conductor to set the tempo and coordinate the timing of all the different events. Each developmental process must thus occur at an appropriate rate, tuned by evolution to fit with the timing of other processes in the embryo or in the environment. The control of timing is one of the most important problems in developmental biology, but also one of the least understood.
Developmental processes are complex, but they are built up from simple steps. A first challenge is to understand the timing of these steps. How long does it take, for example, to switch the expression of a gene on or off? This is not like throwing a light switch: it involves delays. First, it takes time to make an mRNA molecule: the RNA polymerase must travel the length of the gene, the primary RNA transcript must be spliced and otherwise processed, and the resulting mRNA must be exported from the nucleus and delivered to the site where it will be translated. This adds up to what one might call the gestation time of the individual molecule. Second, it takes time for the individual mRNA molecules to accumulate to their fully effective concentration; as explained in Chapter 15, this accumulation time is dictated by the average lifetime of the molecules—the longer they last, the higher their ultimate concentration, and the longer the time taken to attain it. Similar delays occur at the next step, where the mRNA is translated into protein: synthesis of each individual protein molecule involves a gestation delay, and attainment of an effective concentration of protein molecules involves an accumulation delay that depends on the protein’s lifetime. The time for the whole gene switching process is just the sum of the gestation delays and the accumulation delays (basically, the molecular lifetimes) for both the mRNA and the protein molecules. Somewhat counterintuitively, it is the combined length of these delays, rather than the rate of molecular synthesis (the number of molecules synthesized per second), that chiefly determines the switching time.
The same additive principle applies to long cascades of gene switching, where gene A activates gene B, and gene B activates gene C, and so on. It also applies in other circumstances, such as in signaling pathways where one protein directly regulates the activation of the next. In all these cases, molecular lifetimes, along with gestation delays, play a key part in determining the pace of development. The lifetimes of mRNA and protein molecules are enormously variable, from a few minutes or hours to days or more, explaining much of the variation we see in the tempo of developmental events.
Gene switching delays, however, are not the be-all and end-all of developmental timing. Development involves many other kinds of delay that contribute to timing. Chromatin structure takes time to remodel. Inductive signals take time to diffuse across a field of cells (see Figure 21–9). Cells take time to move and rearrange themselves in space. Nevertheless, the timing of gene switching plays a fundamental part in developmental timing, as illustrated in an especially clear and striking way by a gene-expression oscillator that controls the segmentation of the vertebrate body axis, as we now explain.
a Gene-expression Oscillator acts as a clock to control Vertebrate Segmentation