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.

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Available from: Kimimasa Tobita
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    • "During IFT, large particles are transported along the axonemal microtubules from the cell body to the tip of the flagellum and then back to the cell body, where there is a large pool of IFT particles. The IFT particles carry cargo for assembly and maintenance of cilia and flagella (Piperno et al., 1996; Hou et al., 2007; Wren et al., 2013; Craft et al., 2015) and also carry signals between the cilium and the cell body (Pan and Snell, 2003; Goetz and Anderson, 2010; Keady et al., 2012; Liem, Jr. et al., 2012; Eguether et al., 2014). The anterograde, base-to-tip movement of IFT particles is propelled by the microtubule motor kinesin-2 (Kozminski et al., 1995; Scholey, 1996). "
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    ABSTRACT: Drosophila sperm are unusual in that they do not require the intraflagellar transport (IFT) system for assembly of their flagella. In mouse, we find that the IFT proteins are very abundant in testis but mature sperm are completely devoid of them, making the importance of IFT to mammalian sperm development unclear. To address this question, we characterized spermiogenesis and fertility in the Ift88(Tg737Rpw) mouse. This mouse has a hypomorphic mutation in the gene encoding the IFT88 subunit of the IFT particle. This mutation is highly disruptive to ciliary assembly in other organs. Ift88(-/-) mice are completely sterile. They produce ∼350-fold fewer sperm than wild-type mice and the remaining sperm completely lack or have very short flagella. The short flagella rarely have axonemes but assemble ectopic microtubules and outer dense fibers, and accumulate improperly assembled fibrous sheath proteins. Thus, IFT is essential for the formation but not the maintenance of mammalian sperm flagella.
    Preview · Article · Oct 2015 · Molecular biology of the cell
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    • "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 . "
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    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.
    Full-text · Article · Sep 2015 · Developmental Cell
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    • "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). "
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    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.
    Full-text · Article · Apr 2015 · Developmental Cell
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