Repressor Dimerization in the Zebrafish Somitogenesis Clock

The oscillations of the somitogenesis clock are linked to the fundamental process of vertebrate embryo segmentation, yet little is known about their generation. In zebrafish, it has been proposed that Her proteins repress the transcription of their own mRNA. However, in its simplest form, this model is incompatible with the fact that morpholino knockdown of Her proteins can impair expression of their mRNA. Simple self-repression models also do not account for the spatiotemporal pattern of gene expression, with waves of gene expression shrinking as they propagate. Here we study computationally the networks generated by the wealth of dimerization possibilities amongst transcriptional repressors in the zebrafish somitogenesis clock. These networks can reproduce knockdown phenotypes, and strongly suggest the existence of a Her1–Her7 heterodimer, so far untested experimentally. The networks are the first reported to reproduce the spatiotemporal pattern of the zebrafish somitogenesis clock; they shed new light on the role of Her13.2, the only known link between the somitogenesis clock and positional information in the paraxial mesoderm. The networks can also account for perturbations of the clock by manipulation of FGF signaling. Achieving an understanding of the interplay between clock oscillations and positional information is a crucial first step in the investigation of the segmentation mechanism.: Vertebrate embryos acquire a segmented structure along the anteroposterior axis. Segmentation is critical for patterning of other structures (such as nerves, vertebrae, muscles, and blood vessels) and occurs by the rhythmic separation of balls of cells, called somites, from the anterior end of their precursor tissue, called the presomitic mesoderm. These rhythmic events are associated with oscillatory gene expression in the presomitic mesoderm: waves of gene expression originate at the posterior end and spread anteriorly. When a wave reaches the anterior end, a pair of new somites detaches. The set of genes whose expression oscillates is termed the “somitogenesis clock.” Even though the zebrafish somitogenesis clock has been the subject of intensive study, it is not clear how its oscillations are generated. It has been proposed that the mechanism involves a simple negative feedback loop, with proteins of the Her family periodically repressing their own expression. However, this is incompatible with some experimental results and does not explain how the spatiotemporal pattern of gene expression is generated. Here I propose a model—based on physical interactions between Her proteins—that is compatible with experimental results, and that explains how positional information is used to generate the spatiotemporal pattern of gene expression.