Chemical integration of proteins in signaling and development

In developing embryos of eukaryotes, varying concentrations and/or duration of exposure to morphogens induce and repress transcription factors (TFs) in a regular order, thereby acting as signals for cell differentiation. I present a chemical thermodynamic model for the formation and degradation of the morphogen Sonic hedgehog (Shh) and the major TFs involved in dorsal-ventral patterning of the vertebrate neural tube. This two-stage model first considers introduction of Shh into a chemically defined (oxidizing) environment. As the system is driven away from metastable equilibrium, the TFs progressively become more stable than Shh, as indicated by comparison of the calculated overall energies of formation (chemical affinity). In the second stage, a gradual return to metastable equilibrium with Shh drives transitions in the relative stabilities of the TFs that follow the experimental patterns of TF expression. At the intracellular level, the major proteins in the signal transduction network show a metastability progression among reactions of Shh and its cell-surface receptor and the intracellular Gli proteins that act as activators and repressors of transcription. If the endocytosis and degradation of receptor-ligand complexes are coupled to localized protein translation, the consequent thermodynamic constraints may represent a high-level source of specificity that coexists with molecular mechanisms of signal transduction.