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Developmental Biology - Developmental Precision
Cells Determine Their Position Mathematically
Cells find their identity using precise math...
Our bodies are made of many different types of cells arranged in precise spatial patterns that give rise to our tissues and organs. But these cells all began as genetically identical cells, so how do they determine which cell types they should become? A team of researchers at the Institute of Science and Technology Austria, looked for answers in studies of the fruit fly — Drosophila.
They identified that levels of four genes, called gap genes, can be decoded to identify specifications for cell position in the fetus, and published their work in the journal Cell.
In the fruit fly embryo, four gap genes are switched on in various segments along the long axis of its cigar-shaped embryo which form an intricate pattern of stripes. Individual cells in the embryo don't posess a "global plan" of where they are to be located. Scientists therefore hypothesized that a cell somehow measures the concentration of each gap gene, and uses these amounts to determine where cells are and in what concentration. This information might then affect specific functions in that cell.
In the current study Gašper Tkacik PhD, explains: "The signals that cells receive about their position are noisy: the levels of gap gene expression fluctuate over time and between embryos. Given this noise in gap gene concentrations, how precisely could a cell in an embryo perform?
Therefore, researchers measured gap gene expression levels to determine the biological noise within a cell's system. Based on how gap genes are switched on in wild-type (normal) drosophila embryos, they constructed a cell decoder to predict what would happen if any of the 4 gap genes were genetically perturbed, comparing this prediction to the mutant embryos.
The decoder correctly predicted how patterning is distorted in mutant embryos, with 1% accuracy. Optimization of cells allowed each cell to be positioned within one cell of where it should be.
Tkacik: "This result was surprising. Without needing to know the mechanism of how cells determine their position — just making an assumption that it was done optimally and simultaneously, using absolute concentrations of all four gap genes — we can now predict how cell positioning changes in mutants."
Mariela Petkova, a co-first author on the study, was an undergraduate working in Gregor's laboratory when she took on the question of how the cells use genetic and molecular information to find their locations and fates.
"One can imagine cells as GPS devices which, instead of satellite signals, collect molecular ones to figure out their locations. We are able to decode how such molecular signals specify positions along the length of the early fly embryo."
Mariela D. Petkova PhD, Biophysics Graduate Program, Harvard University, Cambridge, Massachusetts, USA.
Scientists have long known that stripes result from a cascade of steps starting with the fly mother. She gives each egg instructions built from three types of signaling molecules. These molecules spread through an embryo to form concentration gradients that activate the four "gap genes" to produce protein molecules that act on DNA segments known as enhancers and drive "pair-rule" genes to produce stripes. Petkova made detailed measurements of gap gene expression and the exact amounts of molecules produced in cells along the long body axis.
With these measurements in hand, the theoretical physicists in the team modelled how the cells use information to find their location in the embryo. The team included co-first author Gašper Tkacik, now a faculty member at the Institute of Science and Technology Austria.
These results question the textbook model of how positional information is conveyed in the Drosophila embryo. Eric Wieschaus and Christiane Nüsslein-Volhard received the Nobel Prize in 1995 for identifying the genes required for patterning. Accordingly, the prevailing view is that very early signals from the mother get refined slowly across several layers of a patterning network.
"Our results question this classic idea of a cascade that progressively refines noisy signals. Already in the earliest step of the cascade, at the level of gap genes, there is enough information to position all cells precisely."
Gašper Tkacik PhD, Assistant Professor, Institute of Science and Technology Austria (IST Austria) Am Campus 1, Austria.
Highlights
• Optimal decoding of gene expression levels can be derived from first principles
• Applied to Drosophila gap genes, it specifies individual cells with 1% precision
• Decoder correctly predicts downstream events in wild-type and mutant embryos
• Molecular logic of gap gene readout must implement nearly optimal computations
Summary
In developing organisms, spatially prescribed cell identities are thought to be determined by the expression levels of multiple genes. Quantitative tests of this idea, however, require a theoretical framework capable of exposing the rules and precision of cell specification over developmental time. We use the gap gene network in the early fly embryo as an example to show how expression levels of the four gap genes can be jointly decoded into an optimal specification of position with 1% accuracy. The decoder correctly predicts, with no free parameters, the dynamics of pair-rule expression patterns at different developmental time points and in various mutant backgrounds. Precise cellular identities are thus available at the earliest stages of development, contrasting the prevailing view of positional information being slowly refined across successive layers of the patterning network. Our results suggest that developmental enhancers closely approximate a mathematically optimal decoding strategy.
Authors
Eric Wieschaus, William Bialek, Mariela Petkova, Gašper Tkacik and senior author Thomas Gregor.
Acknowledgements
This work was supported in part by U.S. National Science Foundation grants PHY-1607612, CCF-0939370 (Center for the Science of Information), and PHY-1734030 (Center for the Physics of Biological Function); by National Institutes of Health grants P50GM071508, R01GM077599 and R01GM097275; by Austrian Science Fund grant FWF P28844; and by a Howard Hughes Medical Institute International Predoctoral Fellowship.
About IST Austria
The Institute of Science and Technology (IST Austria) is a PhD-granting research institution located in Klosterneuburg, 18 km from the center of Vienna, Austria. Inaugurated in 2009, the Institute is dedicated to basic research in the natural and mathematical sciences. IST Austria employs professors on a tenure-track system, postdoctoral fellows, and doctoral students. While dedicated to the principle of curiosity-driven research, the Institute owns the rights to all scientific discoveries and is committed to promote their use. The first president of IST Austria is Thomas A. Henzinger, a leading computer scientist and former professor at the University of California in Berkeley, USA, and the EPFL in Lausanne, Switzerland. The graduate school of IST Austria offers fully-funded PhD positions to highly qualified candidates with a bachelor's or master's degree in biology, neuroscience, mathematics, computer science, physics, and related areas. http://www.ist.ac.at.
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Feb 5, 2019 Fetal Timeline Maternal Timeline News
 Scientists knew that fly cells optimize molecular information available from gap junctions between DNA segments, to establish stripe placement in embryos. But precision of cell signals surprised them by being accurate, despite "noise", to decode cell function or location to within one cell width. Image: Mariela Petkova PhD.
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