IFT25 Links the Signal-Dependent Movement of Hedgehog Components to Intraflagellar Transport

The intraflagellar transport (IFT) system is required for building primary cilia, sensory organelles that cells use to respond to their environment. IFT particles are composed of about 20 proteins, and these proteins are highly conserved across ciliated species. IFT25, however, is absent from some ciliated organisms, suggesting that it may have a unique role distinct from ciliogenesis. Here, we generate an Ift25 null mouse and show that IFT25 is not required for ciliary assembly but is required for proper Hedgehog signaling, which in mammals occurs within cilia. Mutant mice die at birth with multiple phenotypes, indicative of Hedgehog signaling dysfunction. Cilia lacking IFT25 have defects in the signal-dependent transport of multiple Hedgehog components including Patched-1, Smoothened, and Gli2, and fail to activate the pathway upon stimulation. Thus, IFT function is not restricted to building cilia where signaling occurs, but also plays a separable role in signal transduction events. ► IFT25 is not required for cilia assembly ► Ift25 mutant mice die at birth with Hedgehog dysfunction phenotypes ► Ift25 mutant cells are defective in dynamic movements of signaling components In vertebrates, regulators of intraflagellar transport (IFT) and ciliary dynamics are required for Hedgehog signaling. Keady et al. found that IFT25 does not affect ciliary structure but is required for Hedgehog signaling and pathway component dynamics in the cilium. Thus, IFT has separable functions in cilia and in signal transduction.