Deciphering the limits, mechanisms and evolution of developmental robustness using the paradigm of C. elegans seam cell patterning.

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Robustness is the ability of a system to maintain performance in the presence of perturbations. It is a very important principle in engineering, where systems like bridges, aeroplanes or the internet, are designed to withstand a variety of perturbations and retain functionality. Robustness is an equally important property of living systems. However, biological robustness is poorly studied and understood.It is in fact remarkable how biological systems have evolved to perform reproducibly, in the presence of internal and external perturbations. Development, in particular, is highly robust to genetic and environmental variation and this is instrumental for the transformation of a fertilised egg into a multicellular individual. A very striking example of developmental robustness in humans is the presence of five hand digits, a number that is very robust to variation in the genetic composition among individuals or differences in the environment. However, robust systems are not infallible and make mistakes, so cases of poly- or oligodactyly, although rare, do still occur. Such cases represent developmental errors and allow us to quantify the limits of robustness of a particular developmental trait. Robustness is a property that ensures phenotypic stability, and as such, it is very important for system behaviour and evolution. Disease can also be viewed as a breakdown of robustness mechanisms. Therefore, understanding the general principles of what makes a biological system robust is a fundamental problem in biology. To find satisfactory answers to similar basic questions, a common practice is to turn to model systems, where we can easily and rapidly perform a lot of fine experiments. Our favourite system is a small nematode, Caenorhabditis elegans, which is well-known for its simple, fast and highly reproducible development. We propose to focus on a group of epidermal cells of C. elegans, the so-called seam cells, and develop this tissue as a model system to study developmental robustness in animals. These cells have attracted substantial attention because they have stem cell properties, so they divide asymmetrically during larval stages and one daughter cell maintains the proliferating status, whereas the other daughter differentiates into a specialised tissue, such as neurons. As a result of these divisions, wild-type C. elegans adult hermaphrodites have 16 seam cells per lateral side. We would like to characterise the limits of the developmental robustness of this system to genetic (mutations) and environmental variation. Our preliminary data indicate that it is possible to identify mutations that increase seam cell number variation without affecting the mean number of seam cells, so we hope to identify what is the nature of these genes that contribute to ensure phenotypic robustness. We will develop and test hypotheses about how the identified genes play a role in phenotypic robustness and study whether their action is specific for the seam cells or more general to systemic robustness at the whole-animal level. Finally, we will address to what extent our results can be extrapolated to other systems, by studying the evolution of robustness mechanisms in C. briggsae, which is a related nematode species to C. elegans.Our approach will likely enable us to gain insights into the genetic mechanisms and evolution of developmental robustness and derive some general principles about the degree of robustness to quantitative variation in critical regulators and the relative contribution of genes to stabilisation of developmental outcomes. Our goal is to develop broad hypotheses that will be informative to both biomedical scientists interested in robust drug targeting and synthetic biologists who aim at engineering robust biological networks.