Developmental Biology - Segmentation Clocks|
Setting the Speed for Embryo Development
Knowing more about protein stability may help us refine regenerative medicine techniques...
Why do pregnancies last longer in some species than others? Researchers at the Francis Crick Institute have found the clock that sets the speed of embryonic development and discovered this mechanism is based on how proteins are made and dismantled. The study, published in Science, could help us understand how different mammals evolved from one another and help us refine methods for regenerative medicine.
Development Time-Scales Differ
All mammals follow the same steps to grow from embryo to adult. This involves the same series of events, in the same sequence, using similar genes and molecular signals. However, the speed of progress through these steps differs considerably from one species to another. For instance, motor neurons - the nerve cells that control muscle movement - take about three days to develop in mice, but over a week to develop in humans.
To understand what governs this speed in different species, researcher Teresa Rayon and colleagues in James Briscoe's Developmental Dynamics lab at the Crick first grew motor neurons from stem cells in the lab, so they could time the cells' development without any influence from the environment within the embryo.
Using mouse and human stem cells, they saw the same difference in speed between the species. Human motor neurons took more than twice as long as mouse motor neurons to form, so they knew the answer must lie within the cells themselves, not the surrounding environment.
They also checked if the genes were responsible, by introducing human DNA sequences into mouse cells. However, this did not alter the speed of development, so the answer wasn't in the genes either.
Finding Answers in Proteins
Instead, researchers discovered that differences in the speed at which proteins are broken down and replaced explains the difference in speed between the two species. Proteins are constantly turned over - made and dismantled - in cells, and this happens twice as fast in mouse cells compared to human cells. This faster rate of protein turnover in mouse cells accounts for the faster pace of motor neuron formation.
"Human and mouse motor neurons use the same genes and molecules for their embryonic development, it just takes longer for the process to play out in humans. Proteins are simply more stable in humans than mouse embryos and this slows the rate of human development.
It's as if mouse and human embryos are reading the same musical score and playing the same tune but the metronome ticks more slowly in humans than in mice. Now that we've found it, we want to understand how to change its speed."
Teresa Rayon PhD, The Francis Crick Institute, London, United Kingdom.
Impacting Research and Treatment
Understanding the mechanisms that control the speed of development has implications for regenerative medicine and for the use of stem cells in understanding disease.
Being able to speed up or slow down development of stem cells could help refine methods for production of specific types of cells for research and therapeutic applications. It might also help in slowing growth in cells of diseases such as cancer.
James Briscoe, who led the team of researchers adds, "Changes in developmental time ? called heterochronies ? play a profound role in evolution of body shape and size between species. For example, the human brain is larger as its cells grow for a longer period of time during embryonic development, than equivalent cells in mice. Beyond practical applications, understanding how the tempo of embryonic development is controlled, potentially helps us understand how different species evolved."
Setting the tempo for development
Many animals display similarities in their organization (body axis, organ systems, and so on). However, they can display vastly different life spans and thus must accommodate different developmental time scales. Two studies now compare human and mouse development (see the Perspective by Iwata and Vanderhaeghen). Matsuda et al. studied the mechanism by which the human segmentation clock displays an oscillation period of 5 to 6 hours, whereas the mouse period is 2 to 3 hours. They found that biochemical reactions, including protein degradation and delays in gene expression processes, were slower in human cells compared with their mouse counterparts. Rayon et al. looked at the developmental tempo of mouse and human embryonic stem cells as they differentiate to motor neurons in vitro. Neither the sensitivity of cells to signals nor the sequence of gene-regulatory elements could explain the differing pace of differentiation. Instead, a twofold increase in protein stability and cell cycle duration in human cells compared with mouse cells was correlated with the twofold slower rate of human differentiation. These studies show that global biochemical rates play a major role in setting the pace of development.
Teresa Rayon, Despina Stamataki, Ruben Perez-Carrasco, Lorena Garcia-Perez, Christopher Barrington, Manuela Melchionda, Katherine Exelby, Jorge Lazaro, Victor L. J. Tybulewicz, Elizabeth M. C. Fisher, James Briscoe.
Related Article also in this issue of Science
Species-specific segmentation clock periods are due to differetnial biochemical reaction speeds
Although mechanisms of embryonic development are similar between mice and humans, the time scale is generally slower in humans. To investigate these interspecies differences in development, we recapitulate murine and human segmentation clocks that display 2- to 3-hour and 5- to 6-hour oscillation periods, respectively. Our interspecies genome-swapping analyses indicate that the period difference is not due to sequence differences in the HES7 locus, the core gene of the segmentation clock. Instead, we demonstrate that multiple biochemical reactions of HES7, including the degradation and expression delays, are slower in human cells than they are in mouse cells. With the measured biochemical parameters, our mathematical model accounts for the two- to threefold period difference between the species. We propose that cell-autonomous differences in biochemical reaction speeds underlie temporal differences in development between species.
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Sep 22 2020 Fetal Timeline Maternal Timeline News
Researchers at the Francis Crick Institute have found the clock that sets the speed of embryonic development and discovered the mechanism is based on how proteins are made and dismantled.
CREDIT SCIENCE magazine