Loss of the retrograde motor for IFT disrupts localization of Smo to cilia and prevents the expression of both activator and repressor functions of Gli

Abstract

Sonic Hedgehog (Shh) signals are transduced into nuclear ratios of Gli transcriptional activator versus repressor. The initial part of this process is accomplished by Shh acting through Patched (Ptc) to regulate Smoothened (Smo) activity. The mechanisms by which Ptc regulates Smo, and Smo activity is transduced to processing of Gli proteins remain unclear. Recently, a forward genetic approach in mice identified a role for intraflagellar transport (IFT) genes in Shh signal transduction, downstream of Patched (Ptc) and Rab23. Here, we show that the retrograde motor for IFT is required in the mouse for the phenotypic expression of both Gli activator and repressor function and for effective proteolytic processing of Gli3. Furthermore, we show that the localization of Smo to primary cilia is disrupted in mutants. These data indicate that primary cilia act as specialized signal transduction organelles required for coupling Smo activity to the biochemical processing of Gli3 protein.

Activation of the hedgehog-signaling pathway in human cancer and the clinical implications

“…Accumulating evidence from several groups indicate that the primary cilia found on most vertebrate cells have an important but undefined role in the Hh pathway (Huangfu et al, 2003;Corbit et al, 2005;Huangfu and Anderson, 2005;May et al, 2005;Zhang et al, 2005;Hoover et al, 2008). Functions of primary cilium is regulated by large protein complexes involved in intraflagellar transport (IFT), which functions in retrograde and anterograde movement of cargo within the primary cilia (Scholey and Anderson, 2006).…”

“…An SMO mutant lacking ciliary translocation blocks Hh signaling (Corbit et al, 2005). Gli3 processing is significantly affected by IFT mutants (Huangfu and Anderson, 2005;May et al, 2005;Cortellino et al, 2009), suggesting that SMO activates downstream molecules at the cilium. Current data indicate that localization of SMO to cilium is not sufficient to activate hedgehog signaling (Rohatgi et al, 2009;Wilson et al, 2009a).…”

Planar cell polarity effector gene Fuzzy regulates cilia formation and Hedgehog signal transduction in mouse

“…Recent studies indicate that cilia are essential for intracellular transduction of Hedgehog (Hh) signals (Huangfu et al, 2003;Haycraft et al, 2005;Huangfu and Anderson, 2005;Liu et al, 2005;May et al, 2005). The Hh family of secreted proteins (Shh, Dhh, and Ihh) regulates development of multiple organ systems in mammals through a morphogen-like mechanism (Jiang and Hui, 2008).…”

“…Paradoxically, the central nervous system (CNS) is partially dorsalized suggesting a decrease in Hh pathway activity, whereas in the limbs, many digits are observed (polydactyly), suggesting an increased Hh pathway activity. Detailed genetic and biochemical studies indicate that such paradoxical phenotypes result from both a reduction in the proteolytic processing of Gli3 and a failure to activate the Gli activator functions (Haycraft et al, 2005;Huangfu and Anderson, 2005;Liu et al, 2005;May et al, 2005;Jia et al, 2009). Ciliogenesis, or cilia formation, has been best studied in Chlamydomonas and C. elegans (Gerdes et al, 2009).…”

Uncovering the uncharacterized and unexpected: Unbiased phenotype‐driven screens in the mouse

“…IFT proteins are required for the production of cilia, and these studies indicate that cilia are required for normal Hedgehog signaling in the mouse. The role of IFT proteins in Hedgehog signaling is vertebrate-specific, as these genes exist in the Drosophila genome but do not affect Drosophila Hedgehog signaling (Huangfu et al, 2003;Huangfu and Anderson, 2005;May et al, 2005). Spurred on by the success of their T-cell screen, the Goodnow lab has screened for more of the poorly characterized processes that control resistance like self-tolerance and autoimmunity.…”