Sortilin regulates sorting and secretion of Sonic hedgehog

Sonic Hedgehog (Shh) is a secreted morphogen that is an essential regulator of patterning and growth. The Shh full-length protein undergoes autocleavage in the ER to generate the biologically active amino-terminal ShhN fragment, which is destined for secretion. Few receptors have been identified that control the trafficking of this morphogen through the secretory pathway. We identified Sortilin (Sort1), a member of the VPS10P domain receptor family, as a novel Shh trafficking receptor. We demonstrate that Sort/Shh interact using co-IP and proximity ligation in transfected cells and that they co-localize to the Golgi. Sort1 overexpression causes re-distribution of ShhN, and to a lesser extent ShhFL, to the Golgi and reduces Shh secretion. We show loss of Sort1 can partially rescue Hedgehog-associated patterning defects in a mouse model of deficient Shh processing and that Sort1 levels negatively regulate anterograde Shh transport in axons in vitro and Hh-dependent axon-glial interactions in vivo Taken together, we conclude that Shh and Sort1 can interact at the level of the Golgi and that Sort1 directs Shh away from the pathways that promote its secretion.