Comparing the paths of Hedgehog release in artificial and natural settings

The Hedgehog (Hh) family is a central model for signaling gradient formation despite its members undergoing dual N‐ and C‐terminal lipidation during biogenesis. This process strongly binds Hh proteins to the plasma membrane of the cells that produce them, preventing their spontaneous solubilization. Therefore, lipidated Hh proteins require specific molecular mechanisms for their controlled release. Here, we synthesize the available in vivo data on Hh solubilization and dispersion, focusing on three proposed mechanisms centered on the Hh release enhancers Dispatched and Scube2. This approach aims to reconcile conflicting experimental findings on the mechanistic functions of these enhancers, to clarify previous conceptual inconsistencies, and to contribute to a unified understanding of the prerequisites for forming precise Hh gradients.