Journal Article

Morphogen gradient reconstitution reveals Hedgehog pathway design principles

Chen, Siheng, Vachharajani, Vipul, Li, Pulin, Markson, Joseph S., Wang, Sheng, Elowitz, Michael B.

2018

Overview

To translate insights in developmental biology into medical applications, techniques are needed to ensure correct cell localization. Morphogen gradients allow precise and highly reproducible pattern formation during development. Through in vitro experiments and modeling, Li et al. tested the effects of unusual properties of Hedgehog (HH) signaling. The HH morphogen's receptor, Patched (PTCH), sends an inhibitory signal when no ligand is bound, which is relieved by ligand binding. PTCH also regulates spatial distribution of the signal by sequestering the HH ligand. Furthermore, signaling through the receptor promotes synthesis of more inhibitory receptor. These characteristics help speed gradient formation and explain the robustness of the system to changes in the rate of morphogen production. Science , this issue p. 543 Insights from building a morphogen gradient in cell culture are discussed. In developing tissues, cells estimate their spatial position by sensing graded concentrations of diffusible signaling proteins called morphogens. Morphogen-sensing pathways exhibit diverse molecular architectures, whose roles in controlling patterning dynamics and precision have been unclear. In this work, combining cell-based in vitro gradient reconstitution, genetic rewiring, and mathematical modeling, we systematically analyzed the distinctive architectural features of the Sonic Hedgehog pathway. We found that the combination of double-negative regulatory logic and negative feedback through the PTCH receptor accelerates gradient formation and improves robustness to variation in the morphogen production rate compared with alternative designs. The ability to isolate morphogen patterning from concurrent developmental processes and to compare the patterning behaviors of alternative, rewired pathway architectures offers a powerful way to understand and engineer multicellular patterning.

• Publisher: The American Association for the Advancement of Science
• Subject: Animals / Bioengineering / Body Patterning - genetics / Body Patterning - physiology / Cells / Developmental biology / Feedback, Physiological / Hedgehog protein / Hedgehog Proteins - metabolism / Ligands / Localization / Mathematical models / Metabolic Networks and Pathways / Mice / Models, Biological / Negative feedback / NIH 3T3 Cells / Patched protein / Patched-1 Receptor - genetics / Patched-1 Receptor - metabolism / Pattern formation / Patterning / Position sensing / Proteins / Rewiring / Robustness (mathematics) / Sequence Deletion / Sequestering / Signal Transduction / Signaling / Spatial distribution