Targeting Hedgehog to Axons

A number of years ago, we showed that the developing retina controls the timing and size of synaptic target field development in the brain via the axonal transport of two signaling molecules, Hedgehog and Spitz. A third retinal signal called Jelly Belly was recently uncovered by Iris Salecker and colleagues. Hedgehog is partitioned for release at both ends of the photoreceptor neuron. When secreted from the cell body, Hh regulates eye development; when transported along axons and secreted into the brain, Hh controls neuronal development there. The partitioning of Hh for cell body vs. axonal release balances neuronal development between these two fields. We found a conserved amino acid motif located at the Hh C-terminus that targets the protein for axonal release. There is also evidence for an opposing localization signal for cell body release, located at the N-terminus [See publication, Chu et al., 2006]. In ongoing work, we have identified a set of secretory and transport proteins that recognize these signals and control targeted release.  We have also determined, in collaboration with David Robbins (Dartmouth) that some mutant forms of Hedgehog found in human holoprosencephaly are refractory to the Hedgehog auto-cleavage reaction, but retain significant developmental signaling activity in their uncleaved form (Tokhunts et al., 2010, J Biol. Chem.). We are examining the intracellular trafficking and signaling properties of these mutant forms of the protein.