The ESCRT machinery regulates the secretion and long-range activity of Hedgehog

A new role for the endosomal sorting complex required for transport (ESCRT) is identified in fly larvae, where it is shown to be essential for the secretion and long-range signalling of the embryonic development morphogen Hedgehog. ESCRT, the endosomal sorting complex required for transport, is best known for its roles in vesicular trafficking, cell division and mediating viral escape from cells. Pascal Thérond and co-workers now report an unexpected role for this complex. During embryonic development, Hedgehog proteins control tissue patterning and differentiation over short and long distances. The authors find that ESCRT activity is essential for Hedgehog secretion in fly larvae. Pools of Hedgehog and ESCRT are secreted together into the extracellular space and both can subsequently be detected together at the surface of receiving cells, where ESCRT activity seems to be required for long-range Hedgehog signalling. The conserved family of Hedgehog (Hh) proteins acts as short- and long-range secreted morphogens, controlling tissue patterning and differentiation during embryonic development1. Mature Hh carries hydrophobic palmitic acid and cholesterol modifications essential for its extracellular spreading2. Various extracellular transportation mechanisms for Hh have been suggested, but the pathways actually used for Hh secretion and transport in vivo remain unclear. Here we show that Hh secretion in Drosophila wing imaginal discs is dependent on the endosomal sorting complex required for transport (ESCRT)3. In vivo the reduction of ESCRT activity in cells producing Hh leads to a retention of Hh at the external cell surface. Furthermore, we show that ESCRT activity in Hh-producing cells is required for long-range signalling. We also provide evidence that pools of Hh and ESCRT proteins are secreted together into the extracellular space in vivo and can subsequently be detected together at the surface of receiving cells. These findings uncover a new function for ESCRT proteins in controlling morphogen activity and reveal a new mechanism for the transport of secreted Hh across the tissue by extracellular vesicles, which is necessary for long-range target induction.