Graded hedgehog signalling in the neural tube: mathematical modelling of a developmental multistate switch. (360G-Wellcome-080630_Z_06_A)

Morphogens are graded positional cues that control cell fate specification in many developing tissues. The activity of Sonic Hedgehog (Shh) in the spinal cord represents an example where progress has been made in understanding morphogen activity. In response to graded Shh signaling, distinct neuronal subtypes emerge in a precise spatial order from progenitor cells arrayed along the dorsoventral axis of the spinal cord. Cross-repressive interactions between responding genes appear to ensure the generation of discrete changes in gene expression. Thus, graded Shh signalling controls a multiway differentiation switch composed of concentration-dependent gene-regulation and a network of interactions between responding genes. Here we propose to analyse this process using a combination of mathematical and developmental biology. The mechanisms by which a gradient of Shh signalling is formed, refined and interpreted are not well understood. We will construct a mathematical model which describes the formation and interpretation of the Shh gradient. In vitro and in vivo experiments in embryos will be used as the foundation of the model and to test key predictions. The resulting model will be used to analyse how graded Shh effects a multiway switch and to identify critical features of the mechanism that confer precise and reliable patterning.