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

By Courtney J. Haycraft, Boglárka Banizs, Yesim Aydin-Son, Qihong Zhang, E. J. Michaud, B. Yoder. PLoS Genetics, 2005

951 citations recorded by the source corpus.

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.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/26bea8f47570050633ed27d95fc3b14485aa9f9c

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Genetics

1. C. Hui
2. Jin Jiang
3. S. Angers
4. S. Goetz
5. P. Beales
6. Andrew P. McMahon
7. N. Katsanis
8. Courtney J. Haycraft

In Molecular Biology

1. C. Hui
2. Jin Jiang
3. Jussi Taipale
4. Markku Varjosalo
5. G. Fishell
6. P. Ingham
7. F. Balordi
8. Andrew P. McMahon

Citations in the corpus

• The ciliopathies: an emerging class of human genetic disorders. (2006, background): “The authors show that defects in polaris/IFT88 result in the defective processing of the glioma (Gli) transcription factors, more specifically Gli3 processing, and that all Gli proteins localize to both the nucleus as well as the tip of the cilium (36).”
• Pattern formation in the vertebrate neural tube: a sonic hedgehog morphogen-regulated transcriptional network (2008, background): “Furthermore, suppressor of fused (Sufu) and Gli proteins are also present in cilia (Haycraft et al., 2005), and Shh ligand accumulates at the base of the cilium, perhaps in association with Ptch1 (Chamberlain et al., 2008; Corbit et al., 2005; Rohatgi et al., 2007).”
• A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis. (2007, positive): “Notably, in vertebrate cells, the Sonic Hedgehog morphogen requires the intraflagellar transport (IFT) machinery for the transport and processing of its intermediate signaling components at the tip of the primary cilium (Haycraft et al., 2005; May et al., 2005).”
• Hedgehog Signaling in Development and Cancer (2008, positive): “…suggested that the scaffolding role of Cos2 in Drosophila could correspond to that of primary cilia in mammals since the production of Gli R is compromised in mice with defects in the formation and/or function of primary cilia (Haycraft et al., 2005; Huangfu and Anderson, 2005; Liu et al., 2005).”
• Gli proteins in development and disease. (2011, background): “Many signaling components of the Hh pathway are localized within the cilia either under resting conditions or during pathway activation (Corbit et al. 2005, Haycraft et al. 2005, Huangfu & Anderson 2005, Liu et al. 2005).”
• Hedgehog Signaling in the Subventricular Zone Is Required for Both the Maintenance of Stem Cells and the Migration of Newborn Neurons (2007, background): “With regard to Hh signaling, previous studies (Corbit et al., 2005; Haycraft et al., 2005; Huangfu and Anderson, 2005; Liu et al., 2005; May et al., 2005) have found that numerous proteins associated with cilia function (intraflagellar transport proteins) play a role in transduction of Hh…”
• The role of the Hedgehog signaling pathway in cancer: A comprehensive review. (2017, background): “When Hh signaling is induced, Gli proteins also translocate to the PC tip [86].”
• Mechanisms and functions of Hedgehog signalling across the metazoa (2011, background): “, quickly followed by the accumulation of the SUFU–GLI complex at the cilium ti”
• The graded response to Sonic Hedgehog depends on cilia architecture. (2007, background): “Overexpressed Gli1, Gli2, and Gli3 proteins are localized to cilia of primary limb bud cells (Haycraft et al., 2005).”
• The Primary Cilium: A Signaling Center During Vertebrate Development (2010, background): “Both GLI2 , which functions primarily as a transcriptional activator in mammalian Hh signalling, and GLI3 , which can be processed into a repressor, localize to the tips of cili”
• The Primary Cilium as a Complex Signaling Center (2009, background): “Data suggest that the processing of Gli3 to its repressor and the activation of Gli2 in response to Hh binding are dependent on cilia function [62,68]; however, the importance of cilia in Gli2 activity has been called into question recently [69].”