A systems biology approach to axis formation during early zebrafish embryogenesis: from biophysical measurements to model inference

Abstract

During early embryogenesis, secreted proteins dictate the body plan of developing individuals. The resulting patterns are thought to be imposed by a graded distribution of molecular signals. To this day, it is not fully understood how signaling gradients are formed, maintained and adjusted to body sizes of differently sized individuals. This dissertation aims to provide new insights into the biophysical underpinnings of signal molecule gradients of early embryonic patterning and propose novel mechanisms that allow for scale-invariant patterning.

Two of the most important parameters controlling the range and shape of signaling gradients are the rate at which signaling molecules decay and diffuse. Despite their importance, such biophysical parameters have not been measured or have only been assessed under simplified assumptions or contexts for most developmental systems. In this dissertation I present two assays and specialized software packages that allow the assessment of these parameters in living zebrafish embryos.

I then demonstrate how these tools can be used to answer long-standing questions in early embryogenesis, such as how the dorsal-ventral axis is formed. This thesis provides evidence suggesting, in contrast to current hypotheses, that the dorsal-ventral axis is formed by a simple source-sink mechanism.

Moreover, I show how to use mathematical modeling equipped with parameters estimated from the biophysical measurements to describe scale-invariant patterning during germ layer patterning in zebrafish development. My model, together with a rigorous multidimensional parameter screen fitted in normal and articially size-reduced embryos, was able to identify a new mechanism that allows for scaling of the germ layers in differently-sized embryos with realistic parameter congurations.

In summary, this dissertation outlines how a systems biology approach can play a crucial role to advance the understanding of classical open questions in developmental biology.