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Tubby is required for trafficking g protein-coupled receptors to neuronal cilia
Xun Sun, James Haley, Oleg V Bulgakovoleg, Xue Cai, James McGinnis, Tiansen Li
Cilia , 2012, DOI: 10.1186/2046-2530-1-21
Abstract: We used immunofluoresence labeling to examine the subcellular localization of rhodopsin, somatostatin receptor 3 (SSTR3) and melanin concentrating hormone receptor 1 (MCHR1), all of which are G protein-coupled receptors (GPCR), in the retina and brain of wild type (WT) and tubby mutant mice.In tubby mouse retina, rhodopsin is not fully transported across the connecting cilia to the outer segments with ensuing photoreceptor degeneration. In the tubby mouse brain, SSTR3 and MCHR1 fail to localize at the neuronal primary cilia in regions where these receptors play critical roles in neural signaling. The tubby mutant does not manifest a generalized defect in ciliogenesis or protein trafficking.Tubby plays a critical role in trafficking select GPCRs to the cilia. This role is reminiscent of tubby-like proteins 1 and 3, which have been proposed to facilitate trafficking of rhodopsin and select GPCRs in photoreceptors and the developing neural tube, respectively. Thus tubby-like proteins may be generally involved in transciliary trafficking of GPCRs.
Cilia, tubby mice, and obesity
Saikat Mukhopadhyay, Peter K Jackson
Cilia , 2013, DOI: 10.1186/2046-2530-2-1
Abstract:
In Vitro Site Selection of a Consensus Binding Site for the Drosophila melanogaster Tbx20 Homolog Midline  [PDF]
Nima Najand, Jae-Ryeon Ryu, William J. Brook
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0048176
Abstract: We employed in vitro site selection to identify a consensus binding sequence for the Drosophila melanogaster Tbx20 T-box transcription factor homolog Midline. We purified a bacterially expressed T-box DNA binding domain of Midline, and used it in four rounds of precipitation and polymerase-chain-reaction based amplification. We cloned and sequenced 54 random oligonucleotides selected by Midline. Electromobility shift-assays confirmed that 27 of these could bind the Midline T-box. Sequence alignment of these 27 clones suggests that Midline binds as a monomer to a consensus sequence that contains an AGGTGT core. Thus, the Midline consensus binding site we define in this study is similar to that defined for vertebrate Tbx20, but differs from a previously reported Midline binding sequence derived through site selection.
The tubby family proteins
Saikat Mukhopadhyay, Peter K Jackson
Genome Biology , 2011, DOI: 10.1186/gb-2011-12-6-225
Abstract: Monogenic diabetes-obesity syndromes in mice have been historically important in the discovery of genes important in their pathogenesis. The tubby mouse was initially identified as a spontaneous maturity-onset obesity syndrome in inbred backgrounds maintained at the Jackson Laboratory [1]. The mice were later found to be deficient in hearing and vision [2]. Positional cloning strategies by two groups mapped the causative mutation to a novel gene of unknown function called Tub [3,4]. Subsequent studies identified a family of related proteins, present throughout the animal and plant kingdoms, each possessing a signature carboxy-terminal tubby domain capable of highly selective binding to specific phosphoinositides [5,6]. The amino terminus of these proteins is varied and imparts diverse functions to them.The vertebrate family of tubby-like proteins (TULPs) encompasses the founding member TUB and the related TULPs, TULP1 to TULP4. TUB and TULP1-3 are closely related, but TULP4 is more distant [7,8] (Figure 1a). Human TUB and TULP1-3 are 442 to 561 amino acids long and are encoded by 12 to 15 exons spanning 12 to 15 kb. Human TULP4 is longer; its 1,543 amino acids are encoded by 14 exons, spanning around 200 kb. The expression of these genes is also varied and tightly regulated. Tub is expressed broadly in the brain and retina [3,9]. Tulp1 is selectively expressed in the retina [8], whereas Tulp3 is expressed ubiquitously in the mouse embryo [10,11] (Figure 1b). The importance of these genes in mammalian development and physiology is evident from the diseases resulting from their disruption. Mutations in TULP1 cause retinitis pigmentosa in humans [12-14] and retinal degeneration in mice [15], whereas Tulp3 mutants show embryonic lethality with defects in dorso-ventral patterning of the spinal cord [10,16,17].Phylogenetic analysis of the tubby family proteins suggests that the ecdysozoan TUB homologs, such as Drosophila TULP and Caenorhabditis elegans TUB-1, although rel
Cilia - the prodigal organelle
Phil Beales, Peter K Jackson
Cilia , 2012, DOI: 10.1186/2046-2530-1-1
Abstract: So why establish a journal devoted to this once forgotten organelle? The reasons are simple: interest and importance. In 1997-1998 there were a handful of publications citing work on primary cilia with the main focus on olfactory receptors (Figure 1). That year however, saw the publication of Nonaka and Hirokawa's seminal paper on nodal cilia and left-right asymmetry which helped kick-start the field [8]. The year 1998 also produced the classic purification of the intraflagellar transport (IFT) complexes from Cole and Rosenbaum [9], providing the molecular basis for previous discovery from Koszminski and Rosenbaum of the intraflagellar transport process [10]. This led in rapid succession to links between polycystic kidney disease and cilia, starting with the link of C. elegans homolog of the PKD1 and PKD2 polycystins, mutated in human polycystic kidney disease, to sensory cilia [11]; the link of IFT-B components to mutations in left-right asymmetry [12]; and the link between the IFT-B complex, the polycystic kidney disease gene tg737 and ciliary assembly [13]. In 2003, work from Kathryn Anderson's lab made the striking connection between primary cilia and Hedgehog signaling [14], which caught the attention of developmental biologists and helped bring cilia into the mainstream of developmental cell biology. A variety of links between cilia and morphogen pathways have since been published, causing both enthusiasm and controversy. The year 2006 saw a 20-fold increase in publications on the topic with an emphasis on the role of cilia in polycystic kidney disease. Since 2007, a growing number of publications have characterized interacting networks of proteins that form critical parts of the ciliary trafficking and signaling machinery, and linked these networks and complexes to the human genetic disease, providing deeper explanations for human genetic diseases like Bardet-Biedl syndrome, nephronophthisis, Joubert, and Meckel-Gruber syndromes. Publications in 2011 continue
Cilia, Wnt signaling, and the cytoskeleton
Helen L May-Simera, Matthew W Kelley
Cilia , 2012, DOI: 10.1186/2046-2530-1-7
Abstract: The primary cilium had long been ignored by biologists and was considered to be a vestigial remnant of evolution, similar to the human appendix. However, a growing number of human disorders are being attributed to dysfunctions in cilia or cilia-related proteins [1], leading to the term ciliopathies to describe these disorders. Ciliopathies display high degrees of clinical variability, genetic heterogeneity, and phenotypic overlap [2], complicating their discovery and diagnosis. But, in recent years an explosion of data has linked the cilium to several crucial cellular processes and various signaling pathways. Initially cilia were classified as either motile or primary cilia based on their internal structure. Motile cilia were thought to be comprised exclusively of nine outer microtubule doublets with a central pair of microtubules (9+2). In contrast, primary cilia (also referred to as sensory cilia) lack the central microtubule doublets (9+0). Motile cilia are known to be required for mucus clearance, cerebrospinal fluid flow, sperm motility, and leftward flow at the embryonic node, among other functions [3], and defects in this motility are known to be associated with diseases such as Kartagener syndrome (primary ciliary dyskinesia). Primary cilia, in contrast, while expressed on virtually every cell, were considered to be non-functional, evolutionary remnants.More recently, the primary ciliary membrane has been shown to be rich in various channels and receptors [4,5], suggesting that the cilium may serve as the signaling antenna for the cell. In this capacity, cilia might sense developmental morphogens, growth factors, hormones, odorants, and other extracellular signals. Moreover, the cilia-associated basal body complex appears to serve as a gatekeeper for the regulation of downstream intracellular signaling events that are initiated as a result of ciliary receptor activation. As the cilium has no protein synthetic machinery of its own, all the components required
Primary cilia utilize glycoprotein-dependent adhesion mechanisms to stabilize long-lasting cilia-cilia contacts
Carolyn Ott, Natalie Elia, Suh Jeong, Christine Insinna, Prabuddha Sengupta, Jennifer Lippincott-Schwartz
Cilia , 2012, DOI: 10.1186/2046-2530-1-3
Abstract: We identified cilia in rod photoreceptors and cholangiocytes in fixed mouse tissues and examined the structures that these cilia contact in vivo. We then utilized an MDCK cell culture model to characterize the nature of the contacts we observed.In retina and liver tissue, we observed that cilia from nearby cells touch one another. Using MDCK cells, we found compelling evidence that these contacts are stable adhesions that form bridges between two cells, or networks between many cells. We examined the nature and duration of the cilia-cilia contacts and discovered primary cilia movements that facilitate cilia-cilia encounters. Stable adhesions form as the area of contact expands from a single point to a stretch of tightly bound, adjacent cilia membranes. The cilia-cilia contacts persisted for hours and were resistant to several harsh treatments such as proteases and DTT. Unlike many other cell adhesion mechanisms, calcium was not required for the formation or maintenance of cilia adhesion. However, swainsonine, which blocks maturation of N-linked glycoproteins, reduced contact formation. We propose that cellular control of adhesion maintenance is active because cilia adhesion did not prevent cell division; rather, contacts dissolved during mitosis as cilia were resorbed.The demonstration that mammalian primary cilia formed prolonged, direct, physical contacts supports a novel paradigm: that mammalian primary cilia detect features of the extracellular space, not just as passive antennae, but also through direct physical contact. We present a model for the cycle of glycoprotein-dependent contact formation, maintenance, and termination, and discuss the implications for potential physiological functions of cilia-cilia contacts.Cilia extending away from a cell are ideally positioned to passively sample the extracellular environment. Primary cilia, motile cilia, and flagella are structurally and functionally similar microtubule-based organelles. Critical signaling compounds
Smoking Is Associated with Shortened Airway Cilia  [PDF]
Philip L. Leopold,Michael J. O'Mahony,X. Julie Lian,Ann E. Tilley,Ben-Gary Harvey,Ronald G. Crystal
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0008157
Abstract: Whereas cilia damage and reduced cilia beat frequency have been implicated as causative of reduced mucociliary clearance in smokers, theoretically mucociliary clearance could also be affected by cilia length. Based on models of mucociliary clearance predicting that cilia length must exceed the 6–7 μm airway surface fluid depth to generate force in the mucus layer, we hypothesized that cilia height may be decreased in airway epithelium of normal smokers compared to nonsmokers.
Cilia and ciliopathies: From Chlamydomonas and beyond
JunMin Pan
Science China Life Sciences , 2008, DOI: 10.1007/s11427-008-0071-3
Abstract: The biological function of motile cilia/flagella has long been recognized. The non-motile primary cilium, once regarded as a vestigial organelle, however, has been found recently to play unexpected roles in mammalian physiology and development. Defects in cilia have profound impact on human health. Diseases related to cilia, collectively called ciliopathies include male infertility, primary cilia dyskinesia, renal cyst formation, blindness, polydactyly, obesity, hypertension, and even mental retardation. Our current understanding of cilia and ciliopathies has been fueled by basic research employing various model organisms including Chlamydomonas, a unicellular green alga. This review article provides a general introduction to the cell biology of cilia and an overview of various cilia-related diseases.
Intraocular cilia associated with perforating injury  [cached]
Gopal Lingam,Banker Alay,Sharma Tarun,Parikh Sunil
Indian Journal of Ophthalmology , 2000,
Abstract: Purpose: To report a case series of penetrating injury complicated by occurrence of intraocular cilia. Methods: Retrospective analysis of charts of 11 eyes of 11 patients with penetrating injury and intraocular cilia, presenting between September 1978 and November 1998. Ten eyes underwent surgery for trauma-related problems such as cataract, vitritis, retinal detachment etc., at which time intraocular cilia were removed. One eye did not have surgery and continues to harbour cilia at the posterior perforation site. Results: Metallic wire was responsible for injury in 6 of 11 eyes with intraocular cilia. Five eyes had significant intraocular inflammation. The cilia were located in the anterior segment in 4 eyes; in the posterior segment in 6 eyes and in both in one eye. At the last follow up, 72.7% had 6/18 or better vision. Poor vision in the rest was due to recurrent retinal detachment (2 eyes) and macular scarring (1 eye). Conclusion: Intraocular cilia are more commonly associated with injury by a metallic wire. The presentation and management of an injured eye does not seem to be influenced by the presence of cilia in the eye.
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