The best-understood example is in the development of neural precursor cells, or neuroblasts, in the embryonic Drosophila central nervous system. These cells, as we saw, are initially singled out from the neurogenic ectoderm of the embryo by a typical lateral-inhibition mechanism that depends on Notch, and they then proceed through an entirely predictable series of asymmetric cell divisions to generate ganglion mother cells that divide to form neurons and glial cells (see Figure 21–36). The neuroblast changes its internal state as it goes through its set program of divisions, generating different cell types with a reproducible sequence and timing. These successive changes in neuroblast specification occur through the sequential expression of specific transcription regulators. For example, most embryonic neuroblasts sequentially express the transcription regulators Hunchback, Krüppel, Pdm, and Cas in a fixed order (Figure 21–40). When a neuroblast divides, the set of transcription regulators expressed at that time is inherited by the ganglion mother cell and its neural progeny; thus, the differentiated neural cells are endowed with different characters according to their time of birth.
Remarkably, when neuroblasts are taken from an embryo and maintained in culture, isolated from their normal surroundings, they step through much the same stereotyped developmental program as if they had been left in the embryo. Moreover, many of the neuroblast transitions occur even when cell division is blocked. The neuroblasts seem to have a built-in timer that determines when each of the transcription regulators is expressed, and this timer can continue to run in the absence of cell division. The molecular basis of the timing is largely unknown; in part, at least, it must depend on the time taken for gene switching, as described above; but it may well also depend on slow progressive changes in chromatin structure. These too can serve to measure the passage of time in the embryo.
Figure 21–40 Temporal patterning of neuroblast fate in Drosophila.
hunchback, Krüppel, pdm, and cas are transcription regulators that are expressed consecutively in the cell lineage of neuroblasts during development of the Drosophila nervous system. at successive time steps, correlated with cell division, the neuroblast switches its pattern of gene expression. each neuroblast division produces one daughter that remains a neuroblast and expresses the updated set of genes, and one ganglion mother cell that maintains the expression of this gene set and differentiates into specific cell types accordingly. (after B.J. pearson and  c.Q. Doe, Nature 425:624–628, 2003.With permission from Macmillan publishers.) cells rarely count cell Divisions to time their Development
Many specialized cells in animals develop from proliferating progenitor cells that stop dividing and terminally differentiate after a limited number of cell divisions. In these cases, differentiation is coordinated with withdrawal from the cell cycle, but it is usually not known how the coordination is achieved. It has often been suggested that the cell-division cycle might serve as an intracellular timer to control the timing of cell differentiation. The cell cycle would be the ticking clock that sets the tempo of other developmental processes, with maturational changes in gene expression being dependent on cell-cycle progression. Most of the evidence, however, indicates that this tempting idea is wrong. Although there are examples where cells change their maturation state with each division and the change depends on cell division, this is not the general rule. As we just saw for neuroblasts in the Drosophila embryo, cells in developing animals often carry on with their normal timetable of maturation and differentiation even when cell division is artificially blocked; necessarily, some abnormalities occur, if only because a single undivided cell cannot differentiate in two ways at once. But it seems that most developing cells can change their state without a requirement for cell division. Developmental control genes can switch the cell-division-cycle machinery on or off, and it is the dynamics of these genes, rather than the cell cycle, that sets the tempo of development.