In vitro and in vivo investigations of lipid-based signaling mechanisms
Hedgehog (Hh) family members are powerful signaling proteins that – depending on their concentration – determine cellular behaviour in development and disease. To establish the required functional gradient, Hh release from producing cells needs to be tightly controlled. Intriguingly, all Hhs are synthesized as dually lipid-modified molecules that multimerize and firmly tether to the outer membrane leaflet of their producing cells. Crystal lattice contacts suggested that within such a membrane-associated multimer, Hhs create linear chains with 180° turning of every other Hh monomer in the cluster. We hypothesize that this specific geometry results in the engulfing of the Hh multimers within the outer plasma membrane (see figure). In this project, we investigate whether this membrane-engulfment sterically controls Hh release, suggesting a new mode of spatiotemporal morphogen regulation.