How do cilia organize signalling cascades?

Abstract

Cilia and flagella are closely related centriole-nucleated protrusions of the cell with roles in motility and signal transduction. Two of the best-studied signalling pathways organized by cilia are the transduction cascade for the morphogen Hedgehog in vertebrates and the mating pathway that initiates gamete fusion in the unicellular green alga Chlamydomonas reinhardtii . What is the role of cilia in these signalling transduction cascades? In both Hedgehog and mating pathways, all signalling intermediates have been found to localize to cilia, and, for some signalling factors, ciliary localization is regulated by pathway activation. Given a concentration factor of three orders of magnitude provided by translocating a protein into the cilium, the compartment model proposes that cilia act as miniaturized reaction tubes bringing signalling factors and processing enzymes in close proximity. On the other hand, the scaffolding model views the intraflagellar transport machinery, whose primary function is to build cilia and flagella, as a molecular scaffold for the mating transduction cascade at the flagellar membrane. While these models may coexist, it is hoped that a precise understanding of the mechanisms that govern signalling inside cilia will provide a satisfying answer to the question ‘how do cilia organize signalling?’. This review covers the evidence supporting each model of signalling and outlines future directions that may address which model applies in given biological settings.

Isolated polycystic liver disease genes define effectors of polycystin-1 function

“…This was an unexpected localization for polycystic disease gene products since most fibrocystic diseases of the kidney and liver, including ADPKD, are associated with proteins that function in primary cilia (14). Primary cilia are minute solitary membraneenclosed micro tubule-based projections that serve as organelles integrating cellular sensory signals on the apical surface of many cell types, including bile duct and kidney tubule epithelial cells (15)(16)(17). Mutations in another noncilial protein, LDL receptorrelated protein 5 (LRP5), a coreceptor in canonical Wnt signaling, have also been implicated as causing PCLD (18).…”

Regulation of Sufu activity by p66β and Mycbp provides new insight into vertebrate Hedgehog signaling

“…Hh signal transduction in mammals uses the primary cilium (Eggenschwiler and Anderson 2007;Wong and Reiter 2008;Berbari et al 2009;DeRouen and Oro 2009;Goetz and Anderson 2010;Bay and Caspary 2012;Drummond 2012;Oh and Katsanis 2012;Kim and Dynlacht 2013;Nozawa et al 2013;Mukhopadhyay and Rohatgi 2014;Nachury 2014), an evolutionarily conserved microtubule-based organelle analogous to the flagella found in single-celled eukaryotes such as Chlamydomonas reinhardtii (green algae). All core components of vertebrate Hh signaling localize to the primary cilium in a dynamic manner (Corbit et al 2005;Haycraft et al 2005;Rohatgi et al 2007;Chen et al 2009;Endoh-Yamagami et al 2009;Kim et al 2009;Liem et al 2009).…”

The multi-facet aspects of cell sentience and their relevance for the integrative brain actions: role of membrane protein energy landscape

“…Thus, the primary cilium is a sensing organelle functionally separated from the cytoplasm by the ciliary base, which controls the selective entry of ciliary proteins (Wei et al, 2015). A peculiar characteristic of primary cilia is the lack of actin cortex underlying the primary cilium membrane As discussed in the text (see also Nachury, 2014), a special role in the cell sentience can be played by the primary cilium in view of at least four conditions favoring their appropriate cross-talks among signaling molecules: 1. selection of the proteins reaching the cilium thanks a filtering apparatus at the cilium basis; 2. colocation of special signaling molecules in suitable cilium membrane compartments; 3. increased concentrations of signaling molecules in the cilium; 4. specific physicochemical intracilium microenvironment. Left panel: schematic representation of a primary cilium and its main structural peculiarities.…”

“…It has been shown that LRs can concentrate ion channels (Martens et al, 2004) and heterotrimeric G proteins and GPCRs (Allen et al, 2007). Obviously, the co-localization of pathway components permits the efficient transmission of signals between adjacent molecules while avoiding inappropriate cross-talk with other pathways in the cells (Agnati et al, 2007a;Negro et al, 2008). Furthermore, owing to partitioning into LRs, even a small increase in the local concentration of signaling molecules can cause a dramatic amplification of signaling cascades (Simons and Toomre, 2000).…”

“…As discussed above and previously proposed by our group (Agnati et al, 1982(Agnati et al, , 1983(Agnati et al, , 2010bFuxe and Agnati, 1985;Guidolin et al, 2015), GPCR-GPCR receptor-receptor interactions can lead to changes in ligand binding properties, receptor desensitization, and internalization or can even lead to the activation of completely new intracellular decoding molecular pathways. Thus, it can be surmised that primary cilia possess peculiar horizontal molecular networks (HMNs), and the chemical and physical properties of these appendages suggest that cilia represent a specialized cell organelle capable of integrative actions of extracellular signals and of complex crosstalks with the cell cytoplasm (Nachury, 2014;Green and Mykytyn, 2014).…”