Toward a systems-level understanding of the Hedgehog signaling pathway: defining the complex, robust, and fragile

The Hedgehog (Hh) signaling pathway plays a fundamental role in development and tissue homeostasis, governing cell proliferation and differentiation, as well as cell fate. Hh signaling is mediated by an intricate network of proteins that have positive and negative roles that work in concert to fine-tune signaling output. Using feedback loops, redundancy and subcellular compartmentalization, the temporal and spatial dynamics of Hh signaling have evolved to be complex and robust. Yet developmental defects and cancers that arise from perturbation of the Hh pathway reflect specific pathway fragilities. Importantly, these fragile nodes and edges present opportunities for the design of targeted therapies. Despite these significant advances, unconnected molecular links within the Hh pathway still remain, many of which revolve around the dependence of Hh signaling on the primary cilium, an antenna-like sensory organelle. A systems-level understanding of Hh signaling and of ciliary biology will comprehensively define all nodes and edges of the Hh signaling network and will help identify precise therapeutic targets.