The intraflagellar transport A (IFT-A) complex regulates Sonic hedgehog (Shh) signaling by trafficking membrane proteins into primary cilia, Liem et al. reveal.
Vertebrate cells require a primary cilium to activate Shh signaling because many of the pathway's key components accumulate inside these microtubule-based organelles. Primary cilia themselves rely on two multi-subunit transport complexes, IFT-A and IFT-B. IFT-B moves proteins to the tips of cilia, and, in the absence of the complex, cells are unable to form cilia or activate the Shh pathway. IFT-A's main role, on the other hand, has been thought to be the recycling of proteins out of the primary cilium. Mice lacking certain IFT-A subunits have swollen primary cilia and show ectopic Shh activity.
Liem et al. identified two mouse lines with different mutations in the IFT-A subunit ift144. One line, named twinkletoes, expressed a weakly active version of IFT144 and was similar to other IFT-A mutant mice in having slightly larger primary cilia and enhanced Shh signaling. The diamondhead line, however, produced no IFT144 protein, had very short cilia, and showed a decrease in Shh activity. This suggests that, in addition to its recycling function, IFT-A transports proteins into cilia and, like IFT-B, is required for cilia assembly. Indeed, several membrane-associated components of the Shh pathway were missing from the short cilia of diamondhead mice. Soluble pathway components were still present in cilia, however, perhaps indicating a division of labor between IFT-A and IFT-B.
Shh activity may be increased in twinkletoes mice because less adenylyl cyclase is transported into their primary cilia. The researchers propose that this membrane-associated enzyme normally generates cyclic AMP in order to activate protein kinase A, a potent inhibitor of the Shh pathway.