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Another Ingenious Biological Clock Described


The "segmentation clock" is the name given to a control mechanism that regulates body segments in embryogenesis. Most multicellular animals have a segmented form: arthropods have a head, thorax and abdomen; millipedes have a segment for each pair of legs; and we vertebrates, of course, have vertebrae. When an embryo develops, a remarkable "segmentation clock" turns on segment creation, counts the number of segments, then shuts off. More details about this clock were described recently in PLoS Biology.

By studying zebrafish development, a team led by Andrew Oates of the Max Planck Institute of Molecular Cell Biology and Genetics discovered two negative feedback loops that coexist with each other, leading to a robust system that can adapt to environmental changes. "These results suggest that the two redundant, parallel feedback loops form the core circuit of the segmentation clock in zebrafish," Janelle Weaver commented in the same issue of PLoS Biology. "But the two-loop model is more complicated than expected." Weaver explained the basic puzzle behind segmentation:

Rhythms underlie a range of biological phenomena, from circadian clocks to cellular responses to DNA damage. The formation of body parts is no exception. During development, the cyclical expression of genes is crucial for regulating the sequential formation of body segments called somites in vertebrates, including zebrafish. Members of the hes/her family of genes are expressed in a rhythmic fashion during this process, and the oscillations of this genetic network, known as the segmentation clock, guide segmentation and control the speed at which somites form, as well as the number of somites. Models for the origin of oscillations in the zebrafish segmentation clock propose a negative feedback loop involving the her1 and her7 genes. But biochemical evidence supporting this model has been lacking, and exactly how these genes interact to control segmentation and its timing in the zebrafish embryo has been a long-standing mystery.
The Max Planck team explained the essence of the segmentation clock: "The periodicity of somite formation is regulated by the segmentation clock, a genetic oscillator that ticks in the posterior-most embryonic tissue: for each tick of the clock, one new bilateral pair of segments is made." Then they asked the question they wanted to investigate: "The period of the clock appears to determine the number and the length of segments, but what controls this periodicity?"
During vertebrate embryogenesis, the rhythmic and sequential segmentation of the body axis is regulated by an oscillating genetic network termed the segmentation clock. We describe a new dynamic model for the core pace-making circuit of the zebrafish segmentation clock based on a systematic biochemical investigation of the network's topology and precise measurements of somitogenesis dynamics in novel genetic mutants. We show that the core pace-making circuit consists of two distinct negative feedback loops, one with Her1 homodimers and the other with Her7:Hes6 heterodimers, operating in parallel.
The authors modeled a "dimer cloud" of all possible pairings of Her1, Her7 and Hes6 dimers, making the pairings stable and available, whereas only two pairs actually bind to DNA. Within this dynamic circuit, the Her6 protein production oscillates even when Her6 messenger RNA production is constant. "The control of the circuit's dynamics by a population of dimers with and without DNA binding activity is a new principle for the segmentation clock and may be relevant to other biological clocks and transcriptional regulatory networks," they said.

Weaver agreed that this new principle may be common in biology. In saying it is more complicated than expected, she was referring to genetic knockout experiments that produced some counterintuitive results: "Surprisingly, zebrafish with her7 mutations did not segment normally, and these defects disappeared for the most part when her7 mutations existed alongside hes6 mutations." It appears, therefore, that "Hes6 plays a dominant role in guiding segmentation, depending on the availability of the protein's binding partners." Tinkering with the clock is like tweaking a finely tuned watch:

The delicate balance of Hes/Her proteins required for the segmentation clock to function properly is similar to that seen in the genetic network controlling the mouse circadian clock. Moreover, the Hes/Her family of cyclic genes is involved in segmentation in mice and chickens. Thus, the new principle for the segmentation clock may underlie multiple biological clocks and genetic regulatory networks in a range of species.
Common design principles do not necessarily require common ancestry, however. Otherwise, the authors would certainly have said more about it. Weaver didn't mention evolution at all. The Max Planck team offered only one irrelevant mention of evolution tagged onto design phrases. At best, they could only suggest a possible role for evolution somewhere, sometime:
This redundant two-loop topology may provide the circuit with robustness to genetic and environmental perturbation, while the distinct components of each loop could provide the core circuit with independent input and/or output regulatory linkage that might vary with the position of the cell in the PSM, or with developmental stage, or through evolutionary transitions.
Guess how many evolutionary transitions they listed. Hint: it's an integer less than one. But the words topology, circuit, robustness, components, input/output, regulation and linkage are concepts that comport nicely with intelligent design.

Image: Zebrafish, Wikipedia.