Trafficking in and to the primary cilium

Hsiao et al. Cilia 2012, 1:4 http://www.ciliajournal.com/content/1/1/4 REVIEW Open Access Trafficking in and to the primary cilium Yi-Chun Hsiao1,2†, Karina Tuz2† and Russell J Ferland2,3* Abstract Polarized vesicle trafficking is mediated by small GTPase proteins, such as Rabs and Arls/Arfs. These proteins have essential roles in maintaining normal cellular function, in part, through regulating intracellular trafficking. Moreover, these families of proteins have recently been implicated in the formation and function of the primary cilium. The primary cilium, which is found on almost every cell type in vertebrates, is an organelle that protrudes from the surface of the cell and functions as a signaling center. Interestingly, it has recently been linked to a variety of human diseases, collectively referred to as ciliopathies. The primary cilium has an exceptionally high density of receptors on its membrane that are important for sensing and transducing extracellular stimuli. Moreover, the primary cilium serves as a separate cellular compartment from the cytosol, providing for unique spatial and temporal regulation of signaling molecules to initiate downstream events. Thus, functional primary cilia are essential for normal signal transduction. Rabs and Arls/Arfs play critical roles in early cilia formation but are also needed for maintenance of ciliary function through their coordination with intraflagellar transport (IFT), a specialized trafficking system in primary cilia. IFT in cilia is pivotal for the proper movement of proteins into and out of this highly regulated organelle. In this review article, we explore the involvement of polarized vesicular trafficking in cilia formation and function, and discuss how defects in these processes could subsequently lead to the abnormalities observed in ciliopathies. Keywords: Primary cilium, Trafficking, Ciliopathies, Intraflagellar transport, Ciliary signaling Primary cilia are evolutionarily conserved organelles projecting from the plasma membrane in almost every vertebrate cell. In general, primary cilia serve as sensors through which cells receive signals from light, chemical, or mechanical stimuli [1]. Moreover, the involvement of primary cilia in several signaling pathways important for development and tissue homeostasis (including the Sonic hedgehog and Wnt signaling pathways) has attracted much interest and stimulated extensive studies on this ancient cellular structure [2-6]. A functional primary cilium is required to properly activate primary ciliamediated cellular signaling. Therefore, any defects in primary cilia could lead to cellular dysfunction. Indeed, abnormalities in primary cilia have been linked to a constellation of phenotypically and genetically overlapping human diseases, which include Bardet-Biedl syndrome, Joubert syndrome, Meckel-Gruber syndrome, nephronophthisis and Sensenbrenner syndrome; all now * Correspondence: † Contributed equally 2 Albany Medical College, Center for Neuropharmacology and Neuroscience, Albany, NY 12208, USA Full list of author information is available at the end of the article collectively known as ciliopathies [7-10]. The clinical manifestations of these disorders can include brain malformations, skeletal abnormalities, retinal degeneration, and cystic kidney disease. The formation and function of primary cilia are tightly regulated by polarized vesicle trafficking, not only to the primary cilium, but also in coordination with trafficking throughout the entire cell [5]. Although bioinformatic, proteomic and genetic studies have suggested that more than a thousand proteins can be localized at the primary cilium, it is still unclear why and how these proteins work together in this specialized cellular compartment [11-15]. Therefore, studying the formation and function of the primary cilium, through investigations into the function of these ciliary proteins, will help to elucidate the pathophysiological mechanisms responsible for causing the ciliopathies. Structure and function of the primary cilium Cilia are categorized into two classes: motile and nonmotile. Motile cilia, such as tracheal cilia, can be numerous on a cell surface and have the prominent function of moving mucus and fluids, but are not the focus of this © 2012 Hsiao et al; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Hsiao et al. Cilia 2012, 1:4 http://www.ciliajournal.com/content/1/1/4 review. This review focuses on non-motile cilia, also referred to more commonly as primary cilia, which are solitary and mainly serve as a sensory organelle for the cell. Importantly, most primary cilia are non-motile, except for those present in the ventral nodes of vertebrates [1,16]. Primary cilia are polarized structures protruding from the surface of the cell into the extracellular space and are present on almost every quiescent cell in the body. The ciliary axoneme, which is composed of microtubule bundles, is the core structure of the cilium [1]. For primary cilia, the ciliary axoneme consists of a radial array of nine doublet microtubules with no central pair of singlet microtubules, and therefore is called a “9 + 0” configuration. The microtubule axoneme is nucleated at the basal body just beneath the plasma membrane (Figure 1). The basal body is a cytosolic microtubule organizing center that is derived from the mother centriole [1]. All of these structural components of the primary cilium are necessary for the proper formation and function of this signaling structure. Page 2 of 13 Primary cilia are enriched with receptors and provide a separate highly regulated compartment in which signaling events are conveyed from the extracellular space into the cell. Sensing the extracellular environment is a major function of primary cilia. For instance, the ciliated cells of the retina (photoreceptors) and the olfactory system (olfactory sensory neurons) receive and transduce the stimuli of light and odorants to the cells, respectively [17,18]. Primary cilia on the epithelial cells of kidney tubules act as mechanosensors for sensing fluid flow resulting in increased intracellular calcium signaling [19-21]. Recently, a vital role for primary cilia in signaling pathways important for embryonic development and tissue homeostasis has been identified. While the sonic hedgehog (Shh) pathway has been long known as a critical component of neural tube closure and organ patterning during embryonic development, it was only recently discovered that primary cilia are necessary for this signaling [2,6,22]. In mammalian cells when Shh is absent, the Shh receptor, Figure 1 Structure of the primary cilium. The core structure of primary cilia is composed of microtubule bundles (ciliar (...truncated)