Figure 21–44 Temporal control of flowering in Arabidopsis. the Flc gene is active and blocks flowering when plants have been grown without exposure to winterlike temperatures. exposure to a prolonged period of cold leads to the production of the noncoding rNa Coolair, which overlaps with the Flc gene. coolair induces long-term chromatin changes that turn off Flc. these changes persist after the end of the cold period and allow the plant to flower when other environmental conditions are favorable for flowering.
Mutations affecting the regulation of Flc expression alter the time of flowering and thus the ability of a plant to flourish in a given climate. The whole control system governing the switch to flowering is thus of vital importance for agriculture, especially in an era of rapid climate change.
The example of vernalization suggests a general point about the role of chromatin modification in developmental timing. The plant uses changes in chromatin to record its experience of prolonged cold. It may be that in other organisms—animals as well as plants—slow, progressive changes in chromatin structure provide long-term timers for those mysterious developmental processes that unfold slowly, over a period of days, weeks, months, or years. Such chromatin timers may be among the most important clocks in the embryo, but as yet we understand very little about them.
Developmental timing is controlled at many levels. It takes time to switch a gene on or off, and this time delay depends on the lifetimes of the molecules involved, which can vary widely. Cascades of gene regulation involve cascades of delays. Feedback loops can give rise to temporal oscillations in gene expression, and these may serve to generate spatially periodic structures. During vertebrate segmentation, for example, expression of the Hes genes oscillates, and one new pair of somites is formed during each oscillation cycle. Hes genes encode transcription repressor proteins that can act back on expression of the Hes genes themselves. This negative feedback generates oscillations with a period that reflects the delay in the autoregulatory gene switching loop. The period of oscillation of this “segmentation clock” controls the sizes of the somites. Notch signaling between neighboring cells synchronizes their oscillations: when Notch signaling fails, the cells drift out of synchrony because of genetic noise in their individual clocks, and the segmental organization of the vertebral column is disrupted.
Timing does not always depend on cell–cell interactions; many developing animal cells have intrinsic developmental programs that play out even in isolated cells in culture. Neuroblasts in Drosophila embryos, for example, go through set programs of asymmetric divisions, generating different neural cell types at each division with a predictable sequence and timing, through a cascade of gene switching events. Studies in both vertebrates and invertebrates show that such programs are rarely governed by the timing of cell division and can unfold even when cell division is blocked. MicroRNAs produced at critical moments sharpen developmental transitions by blocking the translation and promoting the degradation of specific sets of mRNAs. Global coordination of developmental timing is achieved by hormones: as a tadpole grows, for example, thyroid hormone levels surge and trigger its metamorphosis into a frog. Environmental control of developmental timing is especially striking in plants and reveals the presence of molecular timers that act over the long term. In vernalization, for example, prolonged cold induces changes in chromatin that chart the passage through winter so as to allow flowering only in the spring. Slow, progressive changes in chromatin structure are likely to be important timers in the long-term programming of development in animals too.
The specialization of cells into distinct types at specific times is important, but it is only one aspect of animal development. Equally important are the movements and deformations that cells go through to assemble into tissues and organs with specific shapes and sizes. Like developmental timing, this process of morphogenesis (“form generation”) is less well understood than the processes of differential gene expression and inductive signaling that lead to cell-type specialization. The cell movements can be readily described, but the underlying molecular mechanisms that coordinate the movements are much harder to decipher.