Wnt signaling pathway: from robustness to function

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?


  1. N Barkai, S Leibler, "Robustness in simple biochemical networks", Nature 387:913-917 1997. PubMed
  2. U Alon, M G Surette, N Barkai, S Leibler, "Robustness in bacterial chemotaxis", Nature 397:168-171 1999. PubMed
  3. L Hartwell, "Theoretical biology. A robust view of biochemical pathways", Nature 387:855, 1997.
  4. E Lee, A Salic, R Kruger, R Heinrich, M W Kirschner, "The roles of APC and Axin derived from experimental and theoretical analysis of the Wnt pathway" PLoS Biol 1:E10 2003. PubMed

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