How the cilium appeared is still such a poorly defined question that current hypotheses range from a symbiotic spirochaete to a cellular eye. In this paper, the whole question is subdivided into a list of problems which are morphological, physiological and temporal. These problems are examined one by one, in order to analyse the most popular exogenous hypothesis of Margulis as well as other recent exogenous and endogenous hypotheses. To overcome fundamental topological and temporal difficulties, a new endogenous hypothesis (...) is expounded, according to which the cilium derives from a cellular peduncle reinforced with microtubules. This hypothesis implies a geometrical rationale for the ninefold symmetry. In the last paragraph the consequences of the various hypotheses are compared. (shrink)

In this paper, I review a collection of recently published papers that have provided significant new information about the biogenesis and functions of motile cilia. In vertebrates, the activity of motile cilia has been associated with a fascinating diversity of developmental and physiological processes. Despite the importance, much remains to be learned about the genetic control and cellular events that are involved in the differentiation of motile cilia. We also need to better understand the mechanisms by which cilia‐driven fluid flow (...) is able to influence such a variety of developmental and physiological processes. The Foxj1 family of proteins has now been definitively established as master regulators of motile ciliogenesis.1,2 Identification of the Kintoun/PF13 protein has shed light on the assembly of dynein arms,3 whereas live imaging of ciliary motility has led to the discovery of an intriguing new role for motile cilia in otolith formation in the ear.4. (shrink)

The cilium/flagellum is a sensory-motile organelle ancestrally present in eukaryotic cells. For assembly cilia universally rely on intraflagellar transport (IFT), a specialised bidirectional transport process mediated by the ancestral and conserved IFT complex. Based on the homology of IFT complex proteins to components of coat protein I (COPI) and clathrin-coated vesicles, we propose that the non- vesicular, membrane-bound IFT evolved as a specialised form of coated vesicle transport from a protocoatomer complex. IFT thus shares common ancestry with all protocoatomer (...) derivatives, including all vesicle coats and the nuclear pore complex (NPC). This has major implications for the evolutionary origin of the cilium. First, it reinforces the tenet that duplication and divergence of pre-existing structures, rather than symbiosis, were the major themes during cilium evolution. Second, it suggests that the initial step in the autogenous origin of the cilium was the establishment of a membrane patch with transmembrane proteins transported by the ancestral vesicle-coating IFT complex. We propose a scenario for how the initial membrane patch gradually protruded to enhance exposure to the environment, then started to move, and finally compartmentalised to render receptor signalling and ciliary beating more efficient. BioEssays 28: 191–198, 2006. © 2006 Wiley periodicals, Inc. (shrink)

Cilia are microtubule‐based hair‐like structures that project from the surfaces of eukaryotic cells. Cilium formation relies on intraflagellar transport (IFT) to move ciliary proteins such as tubulin from the site of synthesis in the cell body to the site of function in the cilium. A large protein complex (the IFT complex) is believed to mediate interactions between cargoes and the molecular motors that walk along axonemal microtubules between the ciliary base and tip. A recent study using purified IFT (...) complexes has identified a tubulin‐binding module in the two core IFT proteins IFT74 and IFT81 that likely serves to bind and transport tubulin within cilia. Here, we calculate the amount of tubulin required to support the observed cilium assembly kinetics and explore the possibility of multiple tubulin binding sites within the IFT complex. (shrink)

Kv10.1 is a voltage‐gated potassium channel relevant for tumor biology, but the underlying mechanism is still unclear. We propose that Kv10.1 plays a role coordinating primary cilium disassembly with cell cycle progression through localized changes of membrane potential at the ciliary base. Most non‐dividing cells display a primary cilium, an antenna‐like structure important for cell physiology. The cilium is disassembled when the cell divides, which requires an increase of Ca2+ concentration and a redistribution of phospholipids in its (...) basal region, both of which would be facilitated by local hyperpolarization. Cells lacking Kv10.1 show impaired ciliary disassembly and delayed entrance into mitosis. Kv10.1 is predominantly expressed during G2/M, a critical period for ciliary resorption, and localizes to the ciliary base and vesicles associated with the centrosome. This could explain the influence of Kv10.1 in cell proliferation, as well as phenotypic features of patients carrying gain of function mutations in the gene. (shrink)

Once dismissed as vestigial organelles, primary cilia have garnered the interest of scientists, given their importance in development/signaling, and for their implication in a new disease category known as ciliopathies. However, many, if not all, “cilia” proteins also have locations/functions outside of the primary cilium. These extraciliary functions can complicate the interpretation of a particular ciliopathy phenotype: it may be a result of defects at the cilium and/or at extraciliary locations, and it could be broadly related to a (...) unifying cellular process for these proteins, such as polarity. Assembly of a cilium has many similarities to the development of other polarized structures. This evolutionarily preserved process for the assembly of polarized cell structures offers a perspective on how the cilium may have evolved. We hypothesize that cilia proteins are critical for cell polarity, and that core polarity proteins may have been specialized to form various cellular protrusions, including primary cilia. (shrink)

Protein ubiquitination constitutes a post‐translational modification mediated by ubiquitin ligases whereby ubiquitinated substrates are degraded through the proteasomal or lysosomal pathways, or acquire novel molecular functions according to their “ubiquitin codes.” Dysfunction of the ubiquitination process in cells causes various diseases such as cancers along with neurodegenerative, auto‐immune/inflammatory, and metabolic diseases. KCTD10 functions as a substrate recognition receptor for cullin‐3 (CUL3), a scaffold protein in RING‐type ubiquitin ligase complexes. Recently, studies by ourselves and others have identified new substrates that are (...) ubiquitinated by the CUL3/KCTD10 ubiquitin ligase complex. Moreover, the type of polyubiquitination (e.g., K27‐, K48‐, or K63‐chain) of various substrates (e.g., RhoB, CEP97, EIF3D, and TRIF) mediated by KCTD10 underlies its divergent roles in endothelial barrier formation, primary cilium formation, plasma membrane dynamics, cell proliferation, and immune response. Here, the physiological functions of KCTD10 are summarized and potential mechanisms are proposed. (shrink)

The external surfaces of the human body, as well as its internal organs, constantly experience different kinds of mechanical stimulations. For example, tubular epithelial cells of the kidney are continuously exposed to a variety of mechanical forces, such as fluid flow shear stress within the lumen of th nephron. The majority of epithelial cells along the nephron, except intercalated cells, possess a primary cilium, an organelle projecting from the cell's apical surface into the luminal space. Despite its discovery over (...) 100 years ago, the primary cilium's function continued to elude researchers for many decades. However, recent studies indicate that renal cilia have a sensory function. Studies on polycystic kidney disease (PKD) have identified many of the molecular players, which should help solve the mystery of how the renal cilium senses fluid flow. In this review, we will summarize the recent breakthroughs in PKD research and discuss the role(s) of th polycystin signaling complex in mediating mechanosensory function by the primary cilium of renal epithelium as well as of the embryonic node. BioEssays 26:844–856, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

One major milestone in the development of the sea urchin embryo is the assembly of a single cilium on each blastomere just before hatching. These cilia are constructed both from pre‐existing protein building blocks, such as tubulin and dynein, and from a number of 9+2 architectural elements that are synthesized de novo at ciliogenesis. The finite or quantal synthesis of certain key architectural proteins is coincident with ciliary elongation and proportional to ciliary length. Upon deciliation, the synthesis of architectural (...) proteins occurs anew, a new cilium grows, and the stores of various building blocks are replenished. This routine of coordinated ciliary gene expression may be replayed experimentally many times without delaying normal development. The ability to regenerate cilia has allowed elucidation of these various protein synthetic relationships and has led to the discovery of the pathways by which membrane‐associated tubulin and axoneme‐associated architectural proteins are conveyed into the highly compartmentalized growing cilium. The sea urchin embryo thus provides a very convenient model system for studies of ciliary assembly and maintenance, coordinate gene expression and membrane dynamics. (shrink)

The shape and turnover of photoreceptor membranes appears to depend on associated actin filaments. In dipterans, the photoreceptor membrane is microvillar. It is turned over by the addition of new membrane at the bases of the microvilli and by subsequent shedding, mostly from the distal ends. Each microvillus contains actin filaments as a component of its cytoskeletal core. Two myosin I‐like proteins co‐localize with the actin filaments. It is suggested that one of the myosin I‐like proteins might be linked to (...) the microvillar membrane. By interacting with the actin filaments, this motor should move the membrane of a microvillus in a distal direction, thus providing a possible mechanism for the turnover of the membrane.A vertebrate photoreceptor cell contains a small cluster of actin filaments in its connecting cilium at the site where new transductive disk membranes are formed. Disruption of the actin filaments perturbs disk morphogenesis. The most likely explanation for this perturbation is that the process of initiating a new disk is inhibited. Conventional myosin (myosin II) is found in the connecting cilium with the same distribution as actin. A simple model is proposed to illustrate how the actin–myosin system of the connecting cilium might function to initiate the morphogenesis of a disk membrane. (shrink)

The Arf family proteins are best known for their roles in the vesicle biogenesis. However, they also play fundamental roles in a wide range of cellular regulation besides vesicular trafficking, such as modulation of lipid metabolic enzymes, cytoskeleton remodeling, ciliogenesis, lysosomal, and mitochondrial morphology and functions. Growing studies continue to expand the downstream effector landscape of Arf proteins, especially for the less‐studied members, revealing new biological functions, such as amino acid sensing. Experiments with cutting‐edge technologies and in vivo functional studies (...) in the last decade help to provide a more comprehensive view of Arf family functions. In this review, we summarize the cellular functions that are regulated by at least two different Arf members with an emphasis on those beyond vesicle biogenesis. (shrink)