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

Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Developmental Cell (Impact Factor: 9.71). 05/2012; 22(5):940-51. DOI: 10.1016/j.devcel.2012.04.009
Source: PubMed


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.

Download full-text


Available from: Kimimasa Tobita, Sep 30, 2015
34 Reads
  • Source
    • "The IFT-B protein IFT25, which has no effect on cilia assembly but is required for Hh signaling in vertebrates, is the exception. However, IFT25 is not conserved in Caenorhabditis elegans or Drosophila (Keady et al., 2012). The importance of IFT25 suggests that moving Shh-signaling components along the axoneme (in and out of the cilium) is also critical for Shh signaling in vertebrates, which is again consistent with the notion that Shh signaling needs to take place inside the cilium when cilia are present . "
    [Show abstract] [Hide abstract]
    ABSTRACT: The development of multicellular organisms requires the precisely coordinated regulation of an evolutionarily conserved group of signaling pathways. Temporal and spatial control of these signaling cascades is achieved through networks of regulatory proteins, segregation of pathway components in specific subcellular compartments, or both. In vertebrates, dysregulation of primary cilia function has been strongly linked to developmental signaling defects, yet it remains unclear whether cilia sequester pathway components to regulate their activation or cilia-associated proteins directly modulate developmental signaling events. To elucidate this question, we conducted an RNAi-based screen in Drosophila non-ciliated cells to test for cilium-independent loss-of-function phenotypes of ciliary proteins in developmental signaling pathways. Our results show no effect on Hedgehog signaling. In contrast, our screen identified several cilia-associated proteins as functioning in canonical Wnt signaling. Further characterization of specific components of Intraflagellar Transport complex A uncovered a cilia-independent function in potentiating Wnt signals by promoting β-catenin/Armadillo activity.
    Developmental Cell 09/2015; DOI:10.1016/j.devcel.2015.07.016 · 9.71 Impact Factor
  • Source
    • "Some insights into this process have been recently made by observations that Ptch1 exit from primary cilia requires the function of the intraflagellar transport (IFT) protein Ift25 (Keady et al., 2012), and endocytic turnover mediated by the ubiquitin E3 ligases Smurf1 and Smurf2 (Yue et al., 2014). Loss of these components results in Ptch1 accumulation within primary cilia and reduced cellular responses to Shh (Keady et al., 2012; Yue et al., 2014), reminiscent of the effects seen with the loss of Notch signaling. However, none of these genes were changed by our Notch manipulations (J.H.K. and B.G.N., unpublished data). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Throughout the developing nervous system, neural stem and progenitor cells give rise to diverse classes of neurons and glia in a spatially and temporally coordinated manner. In the ventral spinal cord, much of this diversity emerges through the morphogen actions of Sonic hedgehog (Shh). Interpretation of the Shh gradient depends on both the amount of ligand and duration of exposure, but the mechanisms permitting prolonged responses to Shh are not well understood. We demonstrate that Notch signaling plays an essential role in this process, enabling neural progenitors to attain sufficiently high levels of Shh pathway activity needed to direct the ventral-most cell fates. Notch activity regulates subcellular localization of the Shh receptor Patched1, gating the translocation of the key effector Smoothened to primary cilia and its downstream signaling activities. These data reveal an unexpected role for Notch shaping the interpretation of the Shh morphogen gradient and influencing cell fate determination. Copyright © 2015 Elsevier Inc. All rights reserved.
    Developmental Cell 04/2015; 148(4). DOI:10.1016/j.devcel.2015.03.005 · 9.71 Impact Factor
  • Source
    • "In addition to the inversin compartment, components in other parts of the ciliary structure could also be regulated by changes in ciliary [Ca 2+ ]. An example is IFT 25, a component of the anterograde intraflagellar transport machinery which plays an essential role in trafficking sonic hedgehog signaling components into the primary cilium [70] (Fig. 1). A recent crystallographic study has detected a Ca 2+ binding site in IFT 25, which could regulate the dynamics of IFT25 transport along the ciliary axoneme [71]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The primary cilium is a solitary hair-like organelle on the cell surface that serves as an antenna sensing ever-changing environmental conditions. In this review, we will first recapitulate the molecular basis of the polymodal sensory function of the primary cilia, specifically focusing on transient receptor potential (TRP) channels that accumulate inside the organelle and conduct calcium ions (Ca(2+)). Each subfamily member, namely TRPP2 TRPP3, TRPC1 and TRPV4, is gated by multiple environmental factors, including chemical (receptor ligands, intracellular second messengers such as Ca(2+)), mechanical (fluid shear stress, hypo-osmotic swelling), or physical (temperature, voltage) stimuli. Both activity and heterodimer compositions of the TRP channels may be dynamically regulated for precise tuning to the varying dynamic ranges of the individual input stimuli. We will thus discuss the potential regulation of TRP channels by local second messengers. Despite its reported importance in embryonic patterning and tissue morphogenesis, the precise functional significance of the downstream Ca(2+) signals of the TRP channels remains unknown. We will close our review by featuring recent technological advances in visualizing and analyzing signal transduction inside the primary cilia, together with current perspectives illuminating the functional significance of intraciliary Ca(2+) signals. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Cell calcium 03/2015; 58(4). DOI:10.1016/j.ceca.2015.03.005 · 3.51 Impact Factor
Show more