Accurate reading of morphogen concentrations by nuclear receptors: a formal model of complex transduction pathways.

Signal transduction in development follows multiple, interactive, and overlapping pathways. How does this contribute to accuracy and stability? I show that a formal model of retinoic acid receptors, based on the details of their molecular biology, demonstrates striking precision and robustness while converting a graded morphogen distribution into gene transcription patterns. Thus, transcription can be reliably established in a single row of cells, despite the absence, in the model, of intercellular signalling mechanisms. The subtle interplay of two nuclear receptor types is fundamental for this achievement: one of them ubiquitous, the other controlled itself by morphogen, they act as homodimers or heterodimers, ensuring that many errors cancel out by affecting both activation and repression pathways; regulatory molecular "reservoirs" are also formed. In spite of this robustness, some shifts in gene regulation may well have interesting evolutionary consequences. These conclusions regarding precision in transduction will remain of interest whether retinoic acid turns out to be a morphogen or not, and generalize easily to other experimental situations.