Direct or indirect: the crucial role of N-palmitate in hedgehog signaling

During development, cells use concentration gradients of soluble signaling molecules, called morphogens, to determine their position within tissues and adopt the correct identity. Hedgehog (Hh) morphogens are a key but also unusual example of gradient formation, because their diffusion away from their origin to direct growth and patterning is first prevented by their dual N- and C-terminal lipidation by palmitate and cholesterol. These lipids associate the Hhs with the plasma membrane of the cells that produce them. Later, however, both lipids participate in the spatiotemporal release of Hh by accessory proteins and maintain Hh biofunction in vivo, either directly or indirectly. The present study explores these two mechanistic possibilities, focusing on the central role of N-palmitate in Hh-regulated development in both vertebrates and invertebrates.