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Mechanical force makes precise origami in animal embryos despite “noise”

Mechanic force is a double-edged sword, reining in the noise it itself generates to ensure precise folding of an animal tissue.

A team led by the 2015 HFSP Young Investigator Grant awardees Yu-Chiun Wang from RIKEN Center for Biosystems Dynamics Research (BDR) in Kobe, Japan, and Steffen Lemke from Centre for Organismal Studies (COS) at Heidelberg University, Germany, has discovered that deterministic information alone is insufficient to precisely shape an animal. While animal form is known to depend on precise positional information, cells seem to make use of this information in a surprisingly sloppy way. This sloppiness stems from the intrinsic noise in the force that the cells generate to deform the tissue. Remarkably, however, the force that causes the trouble in the first place self-organizes to rein in the chaos, and a precise animal form can thus emerge. 

The reproducibility of form, shape, and characteristic appearance is a key feature of our development. This is especially true during the early developmental stages when simple tissues are sculpted into complex organs and body parts that are necessary for our survival. While this reproducibility is understood as the work of genetic inheritance, the embryo faces the challenge of genetic variation and developmental “noise” resulting from environmental, physical and chemical fluctuations. Simply put, life is full of noise.

Figure: The origami of the fruit fly embryo – the cephalic furrow – shown at three different scales at an early (t1) and a late (t2) timepoints. The forces that shorten the cells (cellular scale) have a fuzzy distribution across the tissue (tissue scale, left), from which a straight “ribbon” emerges as a result of mechanical self-organization (tissue scale, right) that in turn ensures a straight crease (right, embryo scale).

How developing organisms cope with noise is a question that has fascinated biologists since the dawn of modern genetics. Recent work focusing on the early stages of fruit fly development showed that its instructions – provided in the form of the spatial pattern of gene expression – are information rich and highly precise. It was estimated that the embryo possesses positional information with its resolution down to a single-cell level, while the complex and intertwined relationship among genes, or what biologists call the gene regulatory network, has the ability to filter out noise that comes from genetic variations and environmental fluctuations. In other words, the embryo is capable of generating a detailed, highly reproducible "blueprint", which, if followed accurately, animal forms with great precision and reproducibility can be expected. As appealing as it seems, this idea has rarely been put to a real test. In particular, it was not clear whether such a blueprint can be faithfully executed to ensure the constancy of animal form.

In the study published in Developmental Cell, the team led by Wang and Lemke addressed this question by investigating a structure called the cephalic furrow in the fruit fly embryo, in which the surface of the embryo folds along a straight line in an origami-like fashion. To make this fold, the cells deploy a molecule called myosin to exert mechanical forces that shorten the cells making up the “crease” along which the cephalic furrow folds. While the crease was absolutely straight, it was surprising that on average 20% of the cells did not receive the information to become part of the cephalic furrow. It turned out that the information of where to make a fold was precise, but the reading of this information was unexpectedly sloppy. As a result, myosin distribution was highly variable, resulting in a discrepancy between the blueprint information and cell behavior. 

To find out how the embryo can overcome this sloppiness to make sure that the resultant origami is not crooked or malformed, the team looked more closely and was intrigued by how myosin is distributed across the tissue. On one hand, myosin can be seen in both the cells that make up the crease and their neighbors, hence displaying a “fuzzy” pattern as compared to the crease that is sharp and straight. On the other hand, within each cell myosin shows a bias towards the cell membranes that are parallel to the crease. The team came up with an idea that the force that is generated by this polarized distribution of myosin could allow the cells to engage in a kind of cell-to-cell mechanical communication. Powered by myosin, cell membranes likely pull on each other such that a single and straightened "ribbon”-like structure of linked cell membranes could emerge from this fuzzy pattern of myosin to allow the tissue to fold along a straight line. To test this idea, the team used a sharply focused laser beam to inactivate myosin in a small number of cells. This effectively cut the ribbon and caused the cephalic furrow to develop a kink, indicating that straightness of tissue folding required an intact ribbon that is under tension. Thus, the myosin force self-organizes to overcome the noise that it itself generates. 

These results suggest that the self-organizing property of polarized myosin forces at the tissue scale ensures the straightness, and hence the precision, of the cephalic furrow, overcoming the noise resulting from the sloppy execution of genetic patterning. Theoretical support for this idea came via a collaboration with physicists Fu-Lai Wen and Tatsuo Shibata, also at the RIKEN BDR, who generated a computational model that showed that tissue origami with polarized contractile force always folds the same way despite the presence of noise. Overall, the team concluded that the constancy of animal form requires not just the deterministic process of genetic inheritance and genetic network, but also the stochastic, emergent, and self-organizing properties of mechanical force.

This study reveals a previously overlooked mechanism that ensures the precision and constancy of animal form. The impact that the HFSP grant has on this project cannot be overstated. The generous funds allowed the team to execute an ambitious plan that includes a wide range of cutting-edge experimental, analytical and computational methodologies. The Wang and the Lemke groups have been able to work seamlessly under this unique funding scheme of international collaboration and will continue their collaboration on issues related to the cephalic furrow and beyond.  

Reference

Tissue-Scale Mechanical Coupling Reduces Morphogenetic Noise to Ensure Precision during Epithelial Folding. Anthony S. Eritano, Claire L. Bromley, Antonio Bolea Albero, Lucas Schütz, Fu-Lai Wen, Michiko Takeda, Takashi Fukaya, Mustafa M. Sami, Tatsuo Shibata, Steffen Lemke, and Yu-Chiun Wang. Developmental Cell (2020), https://doi.org/10.1016/j.devcel.2020.02.012.

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Reference

Tissue-Scale Mechanical Coupling Reduces Morphogenetic Noise to Ensure Precision during Epithelial Folding. Anthony S. Eritano, Claire L. Bromley, Antonio Bolea Albero, Lucas Schütz, Fu-Lai Wen, Michiko Takeda, Takashi Fukaya, Mustafa M. Sami, Tatsuo Shibata, Steffen Lemke, and Yu-Chiun Wang. Developmental Cell (2020), https://doi.org/10.1016/j.devcel.2020.02.012.