Biological development is a chaotic affair.
Developing cells come in all sorts of shapes. They may be flat as a pancake, equilateral like a cube or long and skinny like a hose. Developing embryos arise from eggs of different sizes, and they often grow within dynamic environments. Thanks to sexual reproduction and random mutation, they have a variety of genetic signatures. To top it all off, the genetic circuits within the cells are known to be noisy and prone to error. Yet somehow, despite all this chaos, most animals are born perfectly normal.
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“Given this unavoidable noise, how can development give rise to organisms that are so precisely patterned and organized?” said Sean Megason, associate professor of systems biology at Harvard Medical School. “We think the general answer is that there are feedback systems at many levels that monitor the progress of developing tissues and make course corrections along the way to stay on track despite the inevitable variations.”
Think of a biological thermostat, turning on the air conditioning when it gets too hot or the heat when it gets too cold, but instead of maintaining a comfortable room temperature, these feedback loops keep tissues developing smoothly and bodies growing with bilateral symmetry.
In a study reported in the current issue of Cell, Megason and colleagues in the HMS systems biology department and the mathematics department at Susquehanna University, Selinsgrove, Pennsylvania, focused on the question of how the correct three-dimensional shape of cells is produced in an epithelial tissue on the zebra fish embryonic surface called the presumptive enveloping layer (pre-EVL).
Physical interactions and basic geometry play a key role. The team used mathematical tools developed to describe the interactions of soap bubbles to guide their study because, at a fundamental level, cells in a growing tissue act like bubbles forming together on a film of soap. In the early stages of development, when the tissue is sparsely populated and the cells are less crowded, cells sprawl out in flat, pancake-like shapes. As the tissue grows more crowded, the cells are squeezed together, forming cubes and eventually columns.
Using imaging and tracking software that allows the team to monitor each individual cell in the developing embryo, Megason’s team measured cell shape and kept track of how each cell divided. They learned that the shape of a cell controls the direction that the cell divides: When the pre-EVL is sparsely populated and the cells are flat, they’re more likely to divide side by side, increasing the number of cells in the tissues. As the epithelium starts to get crowded, cells are more likely to divide vertically, causing one of the daughter cells to leave during division as they begin forming a new layer underneath the pre-EVL.
The researchers’ computer simulations showed that other parameters, such as surface area and number of cells in the tissue, did not impact cell shape or division patterns. This suggests that these feedback mechanisms may also facilitate flexibility during evolution, Megason said, noting that if a species evolved to grow larger or smaller eggs, the cell-shape threshold mechanism would still regulate the developing tissues to maintain their normal morphology and function.
In the pre-EVL, Megason’s team found that when cells reach a threshold value of around one (when a cell is roughly as wide as it is deep) they shift from being more likely to divide horizontally to being more likely to divide vertically.
Other types of epithelial tissues have different thresholds, Megason said, allowing them to develop with different cell shapes, which might have particular functional benefits. The underlying mechanism that controls cell shape division is likely controlled at the molecular level, with genetic and epigenetic switches that control the orientation of structures within the cells that help organize genetic material during cell division, Megason said.
“In the end, to truly understand the deeper questions, such as how embryos develop robustly, we need to understand the actions and interactions of mechanisms at many different scales—molecular, cellular and tissue,” Megason said.
This work is supported by NIH grants HG004071, DC010791 and GM026875, NIH fellowship 5F32HL097599, a Hearing Health Foundation Emerging Research Grant, a Novartis Fellowship in Systems Biology and by the graduate program of Biological Sciences in Dental Medicine at Harvard University.