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      Gli2 and Gli3 Localize to Cilia and Require the Intraflagellar Transport Protein Polaris for Processing and Function


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          Intraflagellar transport (IFT) proteins are essential for cilia assembly and have recently been associated with a number of developmental processes, such as left–right axis specification and limb and neural tube patterning. Genetic studies indicate that IFT proteins are required for Sonic hedgehog (Shh) signaling downstream of the Smoothened and Patched membrane proteins but upstream of the Glioma (Gli) transcription factors. However, the role that IFT proteins play in transduction of Shh signaling and the importance of cilia in this process remain unknown. Here we provide insights into the mechanism by which defects in an IFT protein, Tg737/Polaris, affect Shh signaling in the murine limb bud. Our data show that loss of Tg737 results in altered Gli3 processing that abrogates Gli3-mediated repression of Gli1 transcriptional activity. In contrast to the conclusions drawn from genetic analysis, the activity of Gli1 and truncated forms of Gli3 (Gli3R) are unaffected in Tg737 mutants at the molecular level, indicating that Tg737/Polaris is differentially involved in specific activities of the Gli proteins. Most important, a negative regulator of Shh signaling, Suppressor of fused, and the three full-length Gli transcription factors localize to the distal tip of cilia in addition to the nucleus. Thus, our data support a model where cilia have a direct role in Gli processing and Shh signal transduction.


          Cilia are small projections extending from the surface of most cells. Research has shown that they are important in diseases such as cystic kidney diseases as well as during the development of many tissues including the limb. More recently, proteins such as Polaris, which is required to build cilia, have been demonstrated to be essential for the regulation of Sonic hedgehog (Shh) signaling, although the mechanism has remained elusive. Precise regulation of Shh signal transduction is important for the proper development of many tissues. Excessive activation of the Shh pathway results in severe developmental defects and has been implicated in certain types of cancer. In the limb, Shh signaling is involved in digit development, and excess signaling leads to the formation of extra digits. The main targets of Shh signaling are the Glioma (Gli) family of transcription factors, and Gli3 has been shown to be processed to a shortened repressor form when Shh signaling is repressed. The localization of the Gli transcription factors and Suppressor of fused, a protein involved in the regulation of Gli protein function, to cilia suggests that the cilia may be an important site for regulation of Shh signal transduction by modulating Gli protein function.

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          Most cited references 22

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          Cilia and Hedgehog responsiveness in the mouse.

          The intraflagellar transport (IFT) proteins Ift172/Wimple and Polaris/Ift88 and the anterograde IFT motor kinesin-II are required for the production and maintenance of cilia. These proteins are also required for the activation of targets of the mouse Hedgehog (Hh) pathway by Gli transcription factors. The phenotypes of the IFT mutants, however, are not identical to mutants that lack Smoothened (Smo), an essential activator of the Hh pathway. We show here that mouse embryos that lack both Ift172 and Smo are identical to Ift172 single mutants, which indicates that Ift172 acts downstream of Smo. Ift172 mutants have a weaker neural patterning phenotype than Smo mutants, because Ift172, but not Smo, is required for proteolytic processing of Gli3 to its repressor form. Dnchc2 and Kif3a, essential subunits of the retrograde and anterograde IFT motors, are also required for both formation of Gli activator and proteolytic processing of Gli3. As a result, IFT mutants display a loss of Hh signaling phenotype in the neural tube, where Gli activators play the major role in pattern formation, and a gain of Hh signaling phenotype in the limb, where Gli3 repressor plays the major role. Because both anterograde and retrograde IFT are essential for positive and negative responses to Hh, and because cilia are present on Hh responsive cells, it is likely that cilia act as organelles that are required for all activity of the mouse Hh pathway.
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            Conservation of the hedgehog/patched signaling pathway from flies to mice: induction of a mouse patched gene by Hedgehog.

            The signaling protein Hedgehog (Hh) controls cell fate and polarizes tissues in both flies and vertebrates. In flies, Hh exerts its effects by opposing the function of a novel transmembrane protein, Patched, while also locally inducing patched (ptc) transcription. We have identified a mouse homolog of ptc which in many tissues is transcribed near cells making either Sonic or Indian hedgehog. In addition, ectopic Sonic hedgehog expression in the mouse central nervous system induces ptc transcription. As in flies, mouse ptc transcription appears to be indicative of hedgehog signal reception. The results support the existence of a conserved signaling pathway used for pattern formation in insects and mammals.
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              The procedure described by Inouye ('76) for the staining of full-term mouse fetal skeletons has been adapted for use with mouse embryos and fetuses of days 14-18 of gestation. The main adaptations for younger specimens involve a longer time in acetone, in lieu of skinning, and omission of the aqueous KOH step. These adaptations require more time but result in consistently good staining of intact specimens.

                Author and article information

                Role: Editor
                PLoS Genet
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                October 2005
                28 October 2005
                26 September 2005
                : 1
                : 4
                [1 ] Department of Cell Biology, University of Alabama, Birmingham, Alabama, United States of America
                [2 ] University of Tennessee Oak Ridge National Laboratory Graduate School of Genome Science and Technology, University of Tennessee, Knoxville, Tennessee, United States of America
                [3 ] Life Sciences Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee, United States of America
                Stanford University School of Medicine, United States of America
                Author notes
                * To whom correspondence should be addressed. E-mail: byoder@ 123456uab.edu
                This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
                Page count
                Pages: 9
                Research Article
                Custom metadata
                Haycraft CJ, Banizs B, Aydin-Son Y, Zhang Q, Michaud EJ, et al. (2005) Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein Polaris for processing and function. PLoS Genet 1(4): e53.



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