31 October 2008
Lea Goentoro
Kirschner Lab
Department of Systems Biology
An important property of a bacterial signaling pathway was shown to be robust to variations in biochemical parameters [1,2]. In response, a conjecture was proposed: given a signaling pathway, one can in principle identify the robust output and hypothesize that it is a property critical for the functioning of the pathway [2,3]. We apply this reverse reasoning to the Wnt pathway, a highly conserved metazoan signaling pathway used throughout development and adulthood. In response to Wnt signal, β-catenin protein accumulates and co-activates transcription. Starting from a published mathematical model [4], we surprisingly find that the absolute level of β-catenin is fine-tuned. The robust output is the fold-change in β-catenin. The robustness is physiologically relevant: measurements in mammalian cells confirm that the Wnt pathway operates within the parameter regime where the robustness prevails. The robust output is functionally relevant: experiments in frog embryos show that robustness in the target gene transcription and morphology correlates with robustness in the fold-change in β-catenin. The robust fold-change, not the fine-tuned level, of β-catenin appears to be the signaling output of the Wnt pathway that dictates downstream transcriptional and phenotypic outcomes. This finding opens up a new avenue of questions. For instance, what does a transcriptional module that reads fold-changes in a transcriptional regulator look like?