(34f) Signal Dynamics in Sonic Hedgehog Tissue Patterning

During embryogenesis, secreted signaling factors, called morphogens, instruct cells to adopt specific mature phenotypes over many cell diameters in processes that may take hours to days. The multiscale mechanisms that morphogen systems employ to establish a precise concentration gradient for patterning tissue architecture are highly complex and are typically analyzed only at long times after secretion (i.e. steady state). We have developed a theoretical model that analyzes dynamically how the intricate transport and signal transduction mechanisms of a model morphogen, Sonic hedgehog (Shh), cooperate in modular fashion to regulate tissue patterning of the developing spinal cord. We build upon a previous single cell model (Lai et al., Biophys J. 2004) and find that the concentration gradient initially established by diffusion can be modified by several long timescale mechanisms, including morphogen binding to extracellular matrix and gene expression. Consistent with numerous recent studies, the model elucidates how the dynamics of gradient formation can be a key determinant of cell response. In addition, this work yields several novel insights into how different transport mechanisms or 'modules' control pattern formation. The model predicts that slowing the transport of a morphogen, such as by lipid modification of the ligand Shh, by ligand binding to proteoglycans, or by the moderate upregulation of dedicated transport molecules like Dispatched, can actually increase the signaling range of the morphogen by concentrating it near the secretion source. Furthermore, several transcriptional targets of Shh, such as Patched and Hedgehog-interacting protein, significantly limit its signaling range by slowing transport and promoting ligand degradation. This investigation suggests that different components can be assembled in a modular fashion to dynamically pattern a morphogen gradient according to the needs of specific tissues.