Sprecher
Beschreibung
Communication between cells is essential for unimpaired metazoan development and physiology. Hedgehogs (Hh) are one example of a highly conserved family of secreted morphogens that regulate vertebrate and invertebrate development directly and in concentration-dependent manner. It is known that Hhs need to associate with heparan sulfate (HS) chains on the plasma membrane of producing cells as one essential prerequisite for their subsequent release and spread through HS-rich tissues. This, in turn, determines Hh gradient formation, gradient range and gradient robustness. The mechanistic basis of HS-regulated Hh gradient formation and function, however, is only poorly understood. Here we use Quartz crystal microbalance with dissipation monitoring (QCM-D) and advanced Drosophila melanogaster genetics to show that HS-mediated Hh spread and gradient formation require directed charge-dependent Hh diffusion on HS and the ability of Hh to switch between HS chains by using two highly conserved HS binding sites. Interfering with one of the two HS binding sites of Hh strongly disturbs Hh gradient robustness and range and leads to ectopic target gene expression, tissue overgrowth and mirror-image duplications of tissues. We suggest that ectopic signaling results from Hh loss from HS into the extracellular space, possibly caused by aborted switching between HS chains during Hh transport. Hh “leakage” would then induce ectopic Hh target gene expression. Finally, we show that HS-restricted Hh diffusion may provide a blueprint for the extracellular transport of a variety of proteins, including morphogens, growth factors of the fibroblast growth factor family, chemokines, or SARS-CoV-2 spike proteins that also bind HS.