Signaling in the primary cilium through the lens of the Hedgehog pathway

Abstract

Cilia are microtubule-based, cell-surface projections whose machinery is evolutionarily conserved. In vertebrates, cilia are observed on almost every cell type and are either motile or immotile. Immotile sensory, or primary cilia, are responsive to extracellular ligands and signals. Cilia can be thought of as compartments, functionally distinct from the cell that provides an environment for signaling cascades. Hedgehog is a critical developmental signaling pathway which is functionally linked to primary cilia in vertebrates. The major components of the vertebrate Hedgehog signaling pathway dynamically localize to the ciliary compartment and ciliary membrane. Critically, G-protein coupled receptor (GPCR) Smoothened, the obligate transducer of the pathway, is enriched and activated in the cilium. While Smoothened is the most intensely studied ciliary receptor, many GPCRs localize within cilia. Understanding the link between Smoothened and cilia defines common features, and distinctions, of GPCR signaling within the primary cilium.

Lysine63-linked ubiquitin chains earmark GPCRs for BBSome-mediated removal from cilia

“…The regulated trafficking of signaling receptors in and out of cilia is a central regulatory mechanism of many cilia-based signaling pathways (Nachury and Mick, 2019; Anvarian et al, 2019; Mykytyn and Askwith, 2017; Gigante and Caspary, 2020). For example, upon activation of the Hedgehog signaling pathway, the Hedgehog receptor Patched 1 and the G protein-coupled receptor (GPCR) GPR161 disappear from cilia while GPCR Smoothened (SMO) accumulates in cilia (Rohatgi et al, 2007; Corbit et al, 2005; Mukhopadhyay et al, 2013).…”

Smoothened Transduces Hedgehog Signals via Activity-Dependent Sequestration of PKA Catalytic Subunits

“…The Hh pathway controls development and regeneration throughout the animal kingdom (Ingham et al, 2011), but whether the underlying transduction mechanism is conserved remains a matter of debate (Huangfu and Anderson, 2006). Recent studies of SMO communication with GLI have emphasized aspects of the Hh pathway that are uniquely important to mammals but not insects, such as the primary cilium (Gigante and Caspary, 2020;Goetz and Anderson, 2010;Huangfu and Anderson, 2006). In contrast, the SMO / PKA-C interaction we describe here is conserved in Drosophila (Li et al, 2014;Ranieri et al, 2014).…”

“…First, GLI transcription is strongly affected by manipulation of either SMO or PKA (Hui and Angers, 2011;Kong et al, 2019;Taipale et al, 2000), complicating efforts to determine whether SMO and PKA reside in the same linear pathway or constitute two separate influences on GLI. Second, during Hh signal transduction, SMO and GLI are subject to elaborate ciliary trafficking mechanisms (Gigante and Caspary, 2020;Goetz and Anderson, 2010) that are incompletely understood and difficult to disentangle from the events occurring immediately downstream of SMO activation. To strip away these potentially confounding factors, we developed a heterologous HEK293 model for SMO regulation of PKA activity.…”

ABbs5mouse model reveals pituitary cilia contributions to developmental abnormalities

“…This study suggests that the loss of Bbs5 specifically in the developing pituitary may be just enough to predispose animals to subtle Hh-associated pituitary abnormalities. This is further supported by disruption of Arl13b signaling in the intermediate region of mutant pituitaries, as Arl13b is also known to regulate Shh signaling events(37,38).Of course, this result does not indicate whether cilia are still present, but unable to traffic Arl13b, or that cilia are absent altogether from the Pars intermedia in mutant mice. Attempts to answer this question included using traditional ciliary markers for ACIII, IFT components, and Acetylated a-tubulin were unsuccessful due to lack of expression of ACIII in the pituitary and difficulty getting the remaining antibodies to work in neuronal tissues.…”