Cinquin Lab

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.

Cinquin O., J. Theor. Biol. 238(3), pp532-540 (2006)

Abstract

The readout of morphogen concentrations has been proposed to be an essential mechanism allowing embryos to specify cell identities (Wolpert Trends Genet 12 (1996) 359), but theoretical and experimental results have led to conflicting ideas as to how useful concentration gradients can be established. In particular, it has been pointed out that some models of passive extracellular diffusion exhibit traveling waves of receptor saturation, inadequate for the establishment of positional information. Two alternative (but not mutually exclusive) models are proposed here, which are based on recent experimental results highlighting the roles of extracellular glycoproteins and morphogen oligomerization. In the first model, inspired from the interactions of Dally and Dally-like with Wingless and Decapentaplegic in the third-instar Drosophila wing disc, two morphogen populations are considered: one in a cell-membrane phase, and another one in an extracellular-matrix phase, which does not interact with receptors; in the second model, inspired from biochemical studies of Sonic Hedgehog, morphogen oligomers are considered to diffuse freely without interacting with receptors. The existence of a dynamic sub-population of freely-diffusing morphogen allows the system to establish a gradient of bound receptor, which is suitable for the specification of positional information. Recent experimental results are discussed within the framework of these models, as well as further possible experiments. The role of Notum in the setup of the Wingless gradient is also shown to be likely not to involve a gradient in Notum distribution, even though Notum is only expressed close to the source of Wingless synthesis.

Cinquin O., J. Theor. Biol. 222(4), pp459-468 (2003)

Abstract

A striking pattern of oscillatory gene expression, related to the segmentation process (somitogenesis), has been identified in chick, mouse, and zebrafish embryos. Somitogenesis displays great autonomy, and it is generally assumed in the literature that somitogenesis-related oscillations are cell-autonomous in chick and mouse. We point out in this article that there would be many biological reasons to expect some mechanism of coupling between cellular oscillators, and we present a model with such coupling, but which also has autonomous properties. Previous experiments can be re-interpreted in light of this model, showing that it is possible to reconcile both autonomous and non-autonomous aspects. We also show that experimental data, previously interpreted as supporting a purely negative-feedback model for the mechanism of the oscillations, is in fact more compatible with this new model, which relies essentially on positive feedback.