How do lifeforms know how to be the right size?
Probing deeply into genetics and biology at the earliest moments of development, researchers found that the size and pattern of an embryo depends on the mother's investment in the egg before it leaves her ovary.
Scientists are very curious about how life forms decide their correct size and proportions. Researchers at Cincinnati Children's Hospital Medical Center reported on March 26 in Nature Communications that they have found new clues to explain this big mystery. Their data from fruit flies shows the size and patterning accuracy of an embryo depends on the amount of resources a mother invests in egg formation.
"One of the most intriguing questions in animal development is something called scaling, or the proportionality of different body parts. Whether you have an elephant or a mouse, for some reason their organ and tissue sizes are generally proportional to the overall size of the body. We want to understand how you get this proportionality."
Jun Ma, PhD, senior author, scientist in the divisions of Biomedical Informatics and Developmental Biology, Cincinnati Children's Hospital Medical Center.
To tackle this age-old and very complex problem, Ma and colleagues studied fruit flies (Drosophila) - one of the simplest forms of animal life. The simplicity of the fruit fly allows scientists to learn fundamental principles about proportional body size in a basic animal leading to mathematical models which can be applied in more advanced life forms such as humans.
A mother fruit fly harnesses genetic and other biological resources in her ovary for the production of eggs. It was found that these resources continue to influence the development of the embryos. Mathematical modeling of this phenomenon is then tested in the lab to complete the developmental picture. In the current study, Ma and colleagues developed a fruit fly model to allow them to measure and mathematically link core processes.
Tissue Expansion-Modulated Maternal Morphogen Scaling, or TEMS, is a protein that forms a concentration of cells along any developing axis in an embryo (one example being the axis from anterior to posterior). An axis restricts gene products to specific parts of the embryo. Under this control mechanism, genes form various body parts or organs specific to that axis.
In the fruit fly, a gene called bicoid produces morphogen which stimulates cells to divde based on the amount of morphogen within that location (Wikipedia). This spurs development of new tissues. The Nature Communications paper is specifically about the fly embryo's proportional scaling from front to back, and just before individual organs begin to form.
The scientists found that the size of fruit fly embryos depends specifically on the growth and size of the 15 egg chambers within the ovary, and on the number of copies of the bicoid gene.
Both of these developmental resources transfer from the oocyte into the future egg. In short, a larger investment in the egg returns a larger embryo with proportional body parts.
When calculating the best number of bicoid gene copies for the mother fly's nurse cells — nurse cells provide nutrients stored in the yolk to the embryo — the scientists saw that the bicoid gene numbers resemble the peak number of cell nuclei in the blastoderm (that layer of cells enclosing the fluid-filled blastocoel cavity of the early embryo). This raises new questions to unravel in future research.
Tissue expansion and patterning are integral to development; however, it is unknown quantitatively how a mother accumulates molecular resources to invest in the future of instructing robust embryonic patterning. Here we develop a model, Tissue Expansion-Modulated Maternal Morphogen Scaling (TEM3S), to study scaled anterior–posterior patterning in Drosophila embryos. Using both ovaries and embryos, we measure a core quantity of the model, the scaling power of the ?Bicoid (?Bcd) morphogen gradient’s amplitude nA. We also evaluate directly model-derived predictions about ?Bcd gradient and patterning properties. Our results show that scaling of the ?Bcd gradient in the embryo originates from, and is constrained fundamentally by, a dynamic relationship between maternal tissue expansion and ?bcd gene copy number expansion in the ovary. This delicate connection between the two transitioning stages of a life cycle, stemming from a finite value of nA~3, underscores a key feature of developmental systems depicted by TEM3S.
Co-first authors on the study were Feng He and Chuanxian Wei, Division of Biomedical Informatics at Cincinnati Children. Also collaborating were researchers from the State Key Laboratory of Brain and Cognitive Sciences (Chinese Academy of Sciences), Beijing, China; the University of Chinese Academy of Sciences, Beijing; and the Sino-French Hoffman Institute (Guangzhou Medical University), Guangzhou, China.
Funding support for the study came from the National Institutes of Health (1R01GM101373) and National Science Foundation (IOS-0843424).
About Cincinnati Children's
Cincinnati Children's Hospital Medical Center ranks third in the nation among all Honor Roll hospitals in U.S. News and World Report's 2014 Best Children's Hospitals. It is also ranked in the top 10 for all 10 pediatric specialties. Cincinnati Children's, a non-profit organization, is one of the top three recipients of pediatric research grants from the National Institutes of Health, and a research and teaching affiliate of the University of Cincinnati College of Medicine. The medical center is internationally recognized for improving child health and transforming delivery of care through fully integrated, globally recognized research, education and innovation.
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