Cinquin Lab

Cinquin O. Mech. Dev. 124(7-8), pp501-517 (2007)

Abstract

The segmentation of vertebrate embryos depends on a complex genetic network that generates highly dynamic gene expression. Many of the elements of the network have been identified, but their interaction and their influence on segmentation remain poorly understood. A few mathematical models have been proposed to explain the dynamics of subsets of the network, but the mechanistic bases remain controversial. This review focuses on outstanding problems with the generation of somitogenesis clock oscillations, and the ways they could regulate segmentation. Proposals that oscillations are generated by a negative feedback loop formed by Lunatic fringe and Notch signaling are weighed against a model based on positive feedback, and the experimental basis for models of simple negative feedback involving Her/Hes genes or Wnt targets is evaluated. Differences are then made explicit between the many ‘clock and wavefront’ model variants that have been proposed to explain how the clock regulates segmentation. An understanding of the somitogenesis clock will require addressing experimentally the many questions that arise from the study of simple models.

Cinquin O. PLoS Computational Biology 3(2) e32 (2007)

Abstract

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.