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1.  The dynamic cilium in human diseases 
PathoGenetics  2009;2:3.
Cilia are specialized organelles protruding from the cell surface of almost all mammalian cells. They consist of a basal body, composed of two centrioles, and a protruding body, named the axoneme. Although the basic structure of all cilia is the same, numerous differences emerge in different cell types, suggesting diverse functions. In recent years many studies have elucidated the function of 9+0 primary cilia. The primary cilium acts as an antenna for the cell, and several important pathways such as Hedgehog, Wnt and planar cell polarity (PCP) are transduced through it. Many studies on animal models have revealed that during embryogenesis the primary cilium has an essential role in defining the correct patterning of the body. Cilia are composed of hundreds of proteins and the impairment or dysfunction of one protein alone can cause complete loss of cilia or the formation of abnormal cilia. Mutations in ciliary proteins cause ciliopathies which can affect many organs at different levels of severity and are characterized by a wide spectrum of phenotypes. Ciliary proteins can be mutated in more than one ciliopathy, suggesting an interaction between proteins. To date, little is known about the role of primary cilia in adult life and it is tempting to speculate about their role in the maintenance of adult organs. The state of the art in primary cilia studies reveals a very intricate role. Analysis of cilia-related pathways and of the different clinical phenotypes of ciliopathies helps to shed light on the function of these sophisticated organelles. The aim of this review is to evaluate the recent advances in cilia function and the molecular mechanisms at the basis of their activity.
doi:10.1186/1755-8417-2-3
PMCID: PMC2694804  PMID: 19439065
2.  Microtubule modifications and stability are altered by cilia perturbation and in cystic kidney disease 
Cytoskeleton (Hoboken, N.J.)  2012;70(1):24-31.
Summary
Disruption of the primary cilium is associated with a growing number of human diseases collectively termed ciliopathies. Ciliopathies present with a broad range of clinical features consistent with the near ubiquitous nature of the organelle and its role in diverse signaling pathways throughout development and adult homeostasis. The clinical features associated with cilia dysfunction can include such phenotypes as polycystic kidneys, skeletal abnormalities, blindness, anosmia, and obesity. Although the clinical relevance of the primary cilium is evident, the effects that cilia dysfunction has on the cell and how this contributes to disease remains poorly understood. Here, we show that loss of ciliogenesis genes such as Ift88 and Kif3a lead to increases in post-translational modifications on cytosolic microtubules. This effect was observed in cilia mutant kidney cells grown in vitro and in vivo in cystic kidneys. The hyper-acetylation of microtubules resulting from cilia loss is associated with both altered microtubule stability and increased α-tubulin acetyl-transferase activity. Intriguingly, the effect on microtubules was also evident in renal samples from patients with autosomal recessive polycystic kidneys. These findings indicate that altered microtubule post-translational modifications may influence some of the phenotypes observed in ciliopathies.
doi:10.1002/cm.21088
PMCID: PMC3552319  PMID: 23124988
cilia; tubulin; acetylation; microtubules; Polycystic Kidney Disease
3.  Primary Cilia: Highly Sophisticated Biological Sensors 
Sensors (Basel, Switzerland)  2009;9(9):7003-7020.
Primary cilia, thin hair-like structures protruding from the apical surface of most mammalian cells, have gained the attention of many researchers over the past decade. Primary cilia are microtubule-filled sensory organelles that are enclosed within the ciliary membrane. They originate at the cell surface from the mother centriole that becomes the mature basal body. In this review, we will discuss recent literatures on the roles of cilia as sophisticated sensory organelles. With particular emphasis on vascular endothelia and renal epithelia, the mechanosensory role of cilia in sensing fluid shear stress will be discussed. Also highlighted is the ciliary involvement in cell cycle regulation, development, cell signaling and cancer. Finally, primary cilia-related disorders will be briefly described.
doi:10.3390/s90907003
PMCID: PMC3290460  PMID: 22423203
primary cilia; mechanosensory transduction; calcium; fluid shear stress
4.  The Primary Cilium: A Signaling Center During Vertebrate Development 
Nature reviews. Genetics  2010;11(5):331-344.
The primary cilium has recently stepped into the spotlight, as a flood of data demonstrate that this organelle has crucial roles in vertebrate development and human genetic diseases. Cilia are required for the response to developmental signals, and evidence is accumulating that the primary cilium is specialized for Hedgehog (Hh) signal transduction. Formation of cilia, in turn, is regulated by other signaling pathways, possibly including the planar cell polarity pathway. The cilium therefore represents a nexus for signaling pathways during development. The connections between cilia and developmental signaling have begun to clarify the basis of human diseases associated with ciliary dysfunction.
doi:10.1038/nrg2774
PMCID: PMC3121168  PMID: 20395968
5.  Building it up and taking it down: the regulation of vertebrate ciliogenesis 
Developmental Dynamics  2008;237(8):1972-1981.
Primary cilia project from the surface of most vertebrate cells, and function in sensation and signaling during both development and adult tissue homeostasis. Mounting evidence links ciliary defects with a wide variety of diseases, underscoring the importance of understanding how these dynamic organelles are assembled and maintained. However, despite their physiological and clinical relevance, the logic and machinery that regulate ciliogenesis remain largely enigmatic. Here, we summarize emerging data that connect the assembly and disassembly of the primary cilium to cell cycle progression and we examine how determinants of cell architecture, including the planar cell polarity pathway, may regulate ciliogenesis. Additionally, identification of the genes underlying diverse ciliopathies in human patients is shedding light on the regulation of the formation of this complex organelle.
doi:10.1002/dvdy.21540
PMCID: PMC3304540  PMID: 18435467
Centriole; centrosome; von Hippel-Lindau; VHL; CP110; Cep97; AuroraA; HEF1; IFT27; MKS1; Meckelin; MKS3
6.  The PCP effector Fuzzy controls cilial assembly and signaling by recruiting Rab8 and Dishevelled to the primary cilium 
Molecular Biology of the Cell  2013;24(5):555-565.
During vertebrate development, the PCP pathway controls multiple cellular processes. Loss of the gene for the PCP effector Fuzzy affects formation of primary cilia via mostly unknown mechanisms. We report that Fuzzy localizes to the primary cilia and orchestrates delivery of Rab8 and Dishevelled to the primary cilium; loss of Fuzzy affects cilia-dependent signaling.
The planar cell polarity (PCP) pathway controls multiple cellular processes during vertebrate development. Recently the PCP pathway was implicated in ciliogenesis and in ciliary function. The primary cilium is an apically projecting solitary organelle that is generated via polarized intracellular trafficking. Because it acts as a signaling nexus, defects in ciliogenesis or cilial function cause multiple congenital anomalies in vertebrates. Loss of the PCP effector Fuzzy affects PCP signaling and formation of primary cilia; however, the mechanisms underlying these processes are largely unknown. Here we report that Fuzzy localizes to the basal body and ciliary axoneme and is essential for ciliogenesis by delivering Rab8 to the basal body and primary cilium. Fuzzy appears to control subcellular localization of the core PCP protein Dishevelled, recruiting it to Rab8-positive vesicles and to the basal body and cilium. We show that loss of Fuzzy results in inhibition of PCP signaling and hyperactivation of the canonical WNT pathway. We propose a mechanism by which Fuzzy participates in ciliogenesis and affects both canonical WNT and PCP signaling.
doi:10.1091/mbc.E12-06-0437
PMCID: PMC3583660  PMID: 23303251
7.  Forkhead Transcription Factor Fd3F Cooperates with Rfx to Regulate a Gene Expression Program for Mechanosensory Cilia Specialization 
Developmental Cell  2012;22(6):1221-1233.
Summary
Cilia have evolved hugely diverse structures and functions to participate in a wide variety of developmental and physiological processes. Ciliary specialization requires differences in gene expression, but few transcription factors are known to regulate this, and their molecular function is unclear. Here, we show that the Drosophila Forkhead box (Fox) gene, fd3F, is required for specialization of the mechanosensory cilium of chordotonal (Ch) neurons. fd3F regulates genes for Ch-specific axonemal dyneins and TRPV ion channels, which are required for sensory transduction, and retrograde transport genes, which are required to differentiate their distinct motile and sensory ciliary zones. fd3F is reminiscent of vertebrate Foxj1, a motile cilia regulator, but fd3F regulates motility genes as part of a broader sensory regulation program. Fd3F cooperates with the pan-ciliary transcription factor, Rfx, to regulate its targets directly. This illuminates pathways involved in ciliary specialization and the molecular mechanism of transcription factors that regulate them.
Graphical Abstract
Highlights
► Fd3F is a Fox transcription factor for mechanosensory ciliary specialization ► Regulates genes for ciliary motility, compartmentalization, and sensory transduction ► Fd3F modulates the activity of the pan-ciliogenic transcription factor, Rfx ► Fd3F is likely related to Foxj1, the vertebrate regulator of motile ciliated cells
Cilia are highly diverse. The motile sensory cilia of Drosophila mechanosensory neurons provide a good model of ciliary structural and functional specialization. Newton et al. show that Fox and Rfx transcription factors work in concert to activate a gene expression program for ciliary specialization in these neurons.
doi:10.1016/j.devcel.2012.05.010
PMCID: PMC3414849  PMID: 22698283
8.  Cilia in the CNS: the Quiet Organelle Claims Center Stage 
Neuron  2011;69(6):1046-1060.
Summary
The primary cilium is a cellular organelle that is almost ubiquitous in eukaryotes, yet its functions in vertebrates have been slow to emerge. The last fifteen years have been marked by accelerating insight into the biology of primary cilia, arising from the synergy of three major lines of research. These research programs describe a specialized mode of protein trafficking in cilia, reveal that genetic disruptions of primary cilia cause complex human disease syndromes, and establish that Sonic hedgehog (Shh) signal transduction requires the primary cilium. New lines of research have branched off to investigate the role of primary cilia in neuronal signaling, adult neurogenesis, and brain tumor formation. We review a fast expanding literature to determine what we now know about the primary cilium in the developing and adult CNS, and what new directions should lead to further clarity.
doi:10.1016/j.neuron.2011.03.002
PMCID: PMC3070490  PMID: 21435552
9.  Proteomic Analysis of Mammalian Primary Cilia 
Current Biology  2012;22(5):414-419.
Summary
The primary cilium is a microtubule-based organelle that senses extracellular signals as a cellular antenna [1]. Primary cilia are found on many types of cells in our body and play important roles in development and physiology. Defects of primary cilia cause a broad class of human genetic diseases called ciliopathies. To gain new insights into ciliary functions and better understand the molecular mechanisms underlying ciliopathies, it is of high importance to generate a catalog of primary cilia proteins. In this study, we isolated primary cilia from mouse kidney cells by using a calcium shock method and identified 195 candidate primary cilia proteins by MudPIT (multidimensional protein identification technology), protein correlation profiling, and subtractive proteomic analysis. Based on comparisons with other proteomic studies of cilia, around 75% of our candidate primary cilia proteins are shared components with motile or specialized sensory cilia. The remaining 25% of the candidate proteins are possible primary cilia specific proteins. These possible primary cilia specific proteins include Evc2, Inpp5e and Inversin, several of which have been linked to known ciliopathies. We have performed the first reported proteomic analysis of primary cilia from mammalian cells. These results provide new insights into primary cilia structure and function.
doi:10.1016/j.cub.2012.01.031
PMCID: PMC3298568  PMID: 22326026
10.  Cauli: A Mouse Strain with an Ift140 Mutation That Results in a Skeletal Ciliopathy Modelling Jeune Syndrome 
PLoS Genetics  2013;9(8):e1003746.
Cilia are architecturally complex organelles that protrude from the cell membrane and have signalling, sensory and motility functions that are central to normal tissue development and homeostasis. There are two broad categories of cilia; motile and non-motile, or primary, cilia. The central role of primary cilia in health and disease has become prominent in the past decade with the recognition of a number of human syndromes that result from defects in the formation or function of primary cilia. This rapidly growing class of conditions, now known as ciliopathies, impact the development of a diverse range of tissues including the neural axis, craniofacial structures, skeleton, kidneys, eyes and lungs. The broad impact of cilia dysfunction on development reflects the pivotal position of the primary cilia within a signalling nexus involving a growing number of growth factor systems including Hedgehog, Pdgf, Fgf, Hippo, Notch and both canonical Wnt and planar cell polarity. We have identified a novel ENU mutant allele of Ift140, which causes a mid-gestation embryonic lethal phenotype in homozygous mutant mice. Mutant embryos exhibit a range of phenotypes including exencephaly and spina bifida, craniofacial dysmorphism, digit anomalies, cardiac anomalies and somite patterning defects. A number of these phenotypes can be attributed to alterations in Hedgehog signalling, although additional signalling systems are also likely to be involved. We also report the identification of a homozygous recessive mutation in IFT140 in a Jeune syndrome patient. This ENU-induced Jeune syndrome model will be useful in delineating the origins of dysmorphology in human ciliopathies.
Author Summary
Skeletal ciliopathies are an emerging field of human disease in which skeletal birth defects arise due to abnormal communication between cells. This failure in communication arises following mutation in components of the primary cilia, a hair-like structure present on every cell. The skeletal ciliopathies are debilitating and in severe cases lead to death in early infancy. However, the mechanisms by which these malformations come about remains unclear. Mouse models are often used to delineate the causes of human birth defects and we have identified a model that mimics one of these conditions known as Jeune syndrome. It is the first mouse model with a mutation in the Ift140 gene, and these mice exhibit phenotypes that are often seen in this set of human syndromes. We have complimented this study with the discovery of a patient that presents with Jeune Syndrome resulting from mutation of human IFT140. This model will allow us to explore the role of IFT140 and the primary cilia in normal human development and provide insight into the field of human skeletal ciliopathies.
doi:10.1371/journal.pgen.1003746
PMCID: PMC3757063  PMID: 24009529
11.  Polycystic Diseases in Visceral Organs 
Primary cilia are nonmotile, microtubule-based, antenna-like organelles projecting from the apical surface of most mammalian cells. Elegant studies have established the importance of ciliary structure and function in signal transduction and the sensory roles of cilia in maintaining healthy cellular state. In particular, dysfunctional cilia have been implicated in a large number of diseases mainly characterized by the presence of fluid-filled cysts in various organs. Aside from polycystic kidney disease (PKD), however, the roles of cilia in polycystic liver disease (PLD), polycystic pancreas disease (PPD), and polycystic ovarian syndrome (PCOS) are still very vague. In addition, although gender and sex hormones are known to regulate cyst formation, their roles in regulating physiological functions of cilia need to be further explored.
doi:10.1155/2011/609370
PMCID: PMC3253486  PMID: 22242024
12.  What are those cilia doing in the neural tube? 
Cilia  2012;1:19.
Primary cilia are present on almost all vertebrate cells, and they have diverse functions in distinct tissues. Cilia are important for sensation in multiple capacities in contexts as different as the retina, kidney, and inner ear. In addition to these roles, cilia play a critical part in various developmental processes. Of particular importance is the development of the neural tube, where cilia are essential for the transduction of the Sonic Hedgehog (Shh) signaling pathway that specifies neuronal cell fates. This relationship is well established and is the most recognizable function for cilia in the neural tube, but it may be part of a larger picture. Here, we discuss the links between cilia and Shh signaling, as well as suggesting additional roles for cilia, and mechanisms for their placement, in the neural tube.
doi:10.1186/2046-2530-1-19
PMCID: PMC3556023  PMID: 23351466
Cilia; neural tube development; PCP signaling; Shh signaling
13.  Photoreceptor sensory cilia and ciliopathies: focus on CEP290, RPGR and their interacting proteins 
Cilia  2012;1:22.
Ciliopathies encompass a broad array of clinical findings associated with genetic defects in biogenesis and/or function of the primary cilium, a ubiquitous organelle involved in the transduction of diverse biological signals. Degeneration or dysfunction of retinal photoreceptors is frequently observed in diverse ciliopathies. The sensory cilium in a photoreceptor elaborates into unique outer segment discs that provide extensive surface area for maximal photon capture and efficient visual transduction. The daily renewal of approximately 10% of outer segments requires a precise control of ciliary transport. Here, we review the ciliopathies with associated retinal degeneration, describe the distinctive structure of the photoreceptor cilium, and discuss mouse models that allow investigations into molecular mechanisms of cilia biogenesis and defects. We have specifically focused on two ciliary proteins – CEP290 and RPGR – that underlie photoreceptor degeneration and syndromic ciliopathies. Mouse models of CEP290 and RPGR disease, and of their multiple interacting partners, have helped unravel new functional insights into cell type-specific phenotypic defects in distinct ciliary proteins. Elucidation of multifaceted ciliary functions and associated protein complexes will require concerted efforts to assimilate diverse datasets from in vivo and in vitro studies. We therefore discuss a possible framework for investigating genetic networks associated with photoreceptor cilia biogenesis and pathology.
doi:10.1186/2046-2530-1-22
PMCID: PMC3563624  PMID: 23351659
Ciliopathy; Retinal degeneration; Primary cilium; Sensory cilia; CEP290; RPGR; Bardet–Biedl syndrome; Leber congenital amaurosis; Joubert syndrome; Nephronophthisis
14.  Evidence for reciliation of RPE1 cells in late G1 phase, and ciliary localisation of cyclin B1☆ 
FEBS Open Bio  2013;3:334-340.
The primary cilium, an organelle that transduces extracellular signals important for development and tissue homeostasis, is typically assembled upon cell cycle exit and disassembled upon cell cycle re-entry. Cilium assembly is thought to be suppressed in cycling cells, however the extent of suppression is not clear. For example, primary cilia are present in certain proliferating cells during development, and a period of reciliation has been reported to occur in late G1 in murine 3T3 cells released from serum starvation-induced quiescence. Human retinal pigmented epithelial (hTERT-RPE1; herein, RPE1) cells are commonly used to investigate pathways regulating cilium disassembly, however the ciliary disassembly profile of these cells remains uncertain. A period of reciliation has not been observed. Here, we analyse the ciliary disassembly profile of RPE1 cells by immunofluorescence microscopy. The results suggest a profile similar to 3T3 cells, including a period of reciliation in late G1 and a second wave of deciliation in S phase. We present evidence that arresting cells in early S phase with hydroxyurea or excess thymidine prevents the second wave of deciliation, and that deciliation is initiated shortly after release from a thymidine block, consistent with coupling to DNA replication. These findings support the often overlooked notion that cilium formation can occur in late G1, and suggest that RPE1 cells could serve as a model system for studying the molecular pathways that direct this process, in addition to those that stimulate cilium disassembly. We also present immunofluorescence data indicating that cyclin B1 localises to primary cilia.
Highlights
•Ciliary disassembly profile of human RPE1 cells was analysed by immunofluorescence.•After release from serum-starvation, RPE1 cells re-assemble cilia in late G1 phase.•Cilium disassembly is not essential for S phase entry, but is coupled to DNA replication.•Cyclin B1 localises to primary cilia.
doi:10.1016/j.fob.2013.08.002
PMCID: PMC3821022  PMID: 24251092
Primary cilia; Cyclin B1; CDK1; Aurora A; DNA replication; Cilium disassembly; AurA, Aurora kinase A; BrdU, bromodeoxyuridine; CDK, cyclin-dependent kinase; DAPI, 4’,6-diamidino-2-phenylindole; FBS, fetal bovine serum; HU, hydroxyurea; Mim, mimosine; siRNA, short interfering RNA; SS, serum-starved; Thy, thymidine
15.  Visualization of live primary cilia dynamics using fluorescence microscopy 
Here we describe methods that are useful for exploring the formation and functions of primary cilia in living cells. First we describe multiple protocols for visualizing solitary cilia that extend away from the cell body. Primary cilia collect, synthesize, and transmit information about the extracellular space into the cell body to promote critical cellular responses. Problems with cilia formation or function can lead to dramatic changes in cell physiology. These methods can be used to assess cilia formation and length, the location of the cilium relative to other cellular structures, and localization of specific proteins to the cilium. The second protocol describes how to quantify movement of fluorescent molecules within the cilium. The microtubules that form the structural scaffold of the cilium are also critical avenues for kinesin and dynein-mediated movement of proteins within the cilium. Assessing intraflagellar dynamics can provide insight into mechanisms of ciliary-mediated signal perception and transmission.
doi:10.1002/0471143030.cb0426s57
PMCID: PMC3690948  PMID: 23208547
Primary cilium; cilia; intraflagellar transport; kymograph
16.  Neuronal ciliary signaling in homeostasis and disease 
Cellular and Molecular Life Sciences  2010;67(19):3287-3297.
Primary cilia are a class of cilia that are typically solitary, immotile appendages present on nearly every mammalian cell type. Primary cilia are believed to perform specialized sensory and signaling functions that are important for normal development and cellular homeostasis. Indeed, primary cilia dysfunction is now linked to numerous human diseases and genetic disorders. Collectively, primary cilia disorders are termed as ciliopathies and present with a wide range of clinical features, including cystic kidney disease, retinal degeneration, obesity, polydactyly, anosmia, intellectual disability, and brain malformations. Although significant progress has been made in elucidating the functions of primary cilia on some cell types, the precise functions of most primary cilia remain unknown. This is particularly true for primary cilia on neurons throughout the mammalian brain. This review will introduce primary cilia and ciliary signaling pathways with a focus on neuronal cilia and their putative functions and roles in human diseases.
doi:10.1007/s00018-010-0425-4
PMCID: PMC3349968  PMID: 20544253
Primary cilia; Ciliopathy; Neuronal cilia; Ciliary signaling; Somatostatin receptor 3; Serotonin receptor 6; Melanin-concentrating hormone receptor 1; Type 3 adenylyl cyclase
17.  RPGR-containing protein complexes in syndromic and non-syndromic retinal degeneration due to ciliary dysfunction 
Journal of genetics  2009;88(4):399-407.
Dysfunction of primary cilia due to mutations in cilia-centrosomal proteins is associated with pleiotropic disorders. The primary (or sensory) cilium of photoreceptors mediates polarized trafficking of proteins for efficient phototransduction. Retinitis pigmentosa GTPase regulator (RPGR) is a cilia-centrosomal protein mutated in >70% of X-linked RP cases and 10%–20% of simplex RP males. Accumulating evidence indicates that RPGR may facilitate the orchestration of multiple ciliary protein complexes. Disruption of these complexes due to mutations in component proteins is an underlying cause of associated photoreceptor degeneration. Here, we highlight the recent developments in understanding the mechanism of cilia-dependent photoreceptor degeneration due to mutations in RPGR and RPGR-interacting proteins in severe genetic diseases, including retinitis pigmentosa, Leber congenital amaurosis (LCA), Joubert syndrome, and Senior–Loken syndrome, and explore the physiological relevance of photoreceptor ciliary protein complexes.
PMCID: PMC3464916  PMID: 20090203
primary cilia; centrosome; transition zone; ciliopathies; photoreceptor; retinal degeneration; retina; RPGR; RP2; CEP290; RPGRIP1L; NPHP
18.  Meckelin Is Necessary for Photoreceptor Intraciliary Transport and Outer Segment Morphogenesis 
This study revealed a role for meckelin in the intraciliary trafficking of phototransduction molecules and in the elongation and maintenance of the photoreceptor outer segments.
Purpose.
Cilia, complex structures found ubiquitously in most vertebrate cells, serve a variety of functions ranging from cell and fluid movement, cell signaling, tissue homeostasis, to sensory perception. Meckelin is a component of ciliary and cell membranes and is encoded by Tmem67 (Mks3). In this study, the retinal morphology and ciliary function in a mouse model for Meckel Syndrome Type 3 (MKS3) throughout the course of photoreceptor development was examined.
Methods.
To study the effects of a disruption in the Mks3 gene on the retina, the authors introduced a functional allele of Pde6b into B6C3Fe a/a-bpck/J mice and evaluated their retinas by ophthalmoscopic, histologic, and ultrastructural examination. In addition, immunofluorescence microscopy was used to assess protein trafficking through the connecting cilium and to examine the localization of ciliary and synaptic proteins in Tmem67bpck mice and controls.
Results.
Photoreceptors degenerate early and rapidly in bpck/bpck mutant mice. In addition, phototransduction proteins, such as rhodopsin, arrestin, and transducin, are mislocalized. Ultrastructural examination of photoreceptors reveal morphologically intact connecting cilia but dysmorphic and misoriented outer segment (OS) discs, at the earliest time point examined.
Conclusions.
These findings underscore the important role for meckelin in intraciliary transport of phototransduction molecules and their effects on subsequent OS morphogenesis and maintenance.
doi:10.1167/iovs.11-8766
PMCID: PMC3317434  PMID: 22247471
19.  Rer1p maintains ciliary length and signaling by regulating γ-secretase activity and Foxj1a levels 
The Journal of Cell Biology  2013;200(6):709-720.
Rer1p is an ER/cis-Golgi membrane protein that maintains ciliary length and function by reducing γ-secretase complex assembly and activity (thereby balancing Notch signaling) and increasing Foxj1a expression.
Cilia project from the surface of most vertebrate cells and are important for several physiological and developmental processes. Ciliary defects are linked to a variety of human diseases, named ciliopathies, underscoring the importance of understanding signaling pathways involved in cilia formation and maintenance. In this paper, we identified Rer1p as the first endoplasmic reticulum/cis-Golgi–localized membrane protein involved in ciliogenesis. Rer1p, a protein quality control receptor, was highly expressed in zebrafish ciliated organs and regulated ciliary structure and function. Both in zebrafish and mammalian cells, loss of Rer1p resulted in the shortening of cilium and impairment of its motile or sensory function, which was reflected by hearing, vision, and left–right asymmetry defects as well as decreased Hedgehog signaling. We further demonstrate that Rer1p depletion reduced ciliary length and function by increasing γ-secretase complex assembly and activity and, consequently, enhancing Notch signaling as well as reducing Foxj1a expression.
doi:10.1083/jcb.201208175
PMCID: PMC3601348  PMID: 23479743
20.  Ciliary Transition Zone (TZ) Proteins RPGR and CEP290: Role in Photoreceptor Cilia and Degenerative Diseases 
Introduction
Primary cilia are microtubule-based extensions of the plasma membrane in nearly all cell types. In vertebrate photoreceptors, the sensory cilium develops as outer segment (OS) that contains the photopigment Rhodopsin and other proteins necessary for phototransduction. The distinct composition of proteins and lipids in the OS membrane is maintained by the selective barrier located at the border between the basal body and the ciliary compartment, called the Transition Zone (TZ).
Areas covered
In this review, we will discuss the identification and function of two ciliary TZ proteins, RPGR (retinitis pigmentosa GTPase regulator) and CEP290. Mutations in these proteins account for a majority of retinopathies due to ciliary dysfunction. We will also discuss the potential of such information in designing therapeutic approaches to treat cilia-dependent photoreceptor degenerative diseases.
Expert opinion
RPGR and CEP290 perform overlapping yet distinct functions in regulating trafficking of cargo via the TZ of photoreceptors. While RPGR modulates the trafficking by acting as a GEF for the small GTPase RAB8A, CEP290 may be involved in maintaining the polarized distribution of proteins in the OS by modulating intracellular levels of selected proteins involved in inhibiting OS formation.
doi:10.1517/14728222.2012.680956
PMCID: PMC3724338  PMID: 22563985
Ciliopathies; cilia; retina; retinitis pigmentosa; retinal degeneration; Leber congenital amaurosis; Ciliary trafficking; connecting cilium; transition zone
21.  Primary Cilia: Cellular Sensors for the Skeleton 
The primary cilium is a solitary, immotile cilium that is present in almost every mammalian cell type. Primary cilia are thought to function as chemosensors, mechanosensors, or both, depending on cell type, and have been linked to several developmental signaling pathways. Primary cilium malfunction has been implicated in several human diseases, the symptoms of which include vision and hearing loss, polydactyly, and polycystic kidneys. Recently, primary cilia have also been implicated in the development and homeostasis of the skeleton. In this review, we discuss the structure and formation of the primary cilium and some of the mechanical and chemical signals to which it could be sensitive, with a focus on skeletal biology. We also raise several unanswered questions regarding the role of primary cilia as mechanosensors and chemosensors and identify potential research avenues to address these questions.
doi:10.1002/ar.20754
PMCID: PMC2879613  PMID: 18727074
primary cilium; kidneys; cilia
22.  Control of vertebrate intraflagellar transport by the planar cell polarity effector Fuz 
The Journal of Cell Biology  2012;198(1):37-45.
The planar cell polarity effector Fuz is required for normal particle dynamics of the intraflagellar transport system, specifically in the retrograde transport of proteins.
Cilia play key roles in development and homeostasis, and defects in cilia structure or function lead to an array of human diseases. Ciliogenesis is accomplished by the intraflagellar transport (IFT) system, a set of proteins governing bidirectional transport of cargoes within ciliary axonemes. In this paper, we present a novel platform for in vivo analysis of vertebrate IFT dynamics. Using this platform, we show that the planar cell polarity (PCP) effector Fuz was required for normal IFT dynamics in vertebrate cilia, the first evidence directly linking PCP to the core machinery of ciliogenesis. Further, we show that Fuz played a specific role in trafficking of retrograde, but not anterograde, IFT proteins. These data place Fuz in the small group of known IFT effectors outside the core machinery and, additionally, identify Fuz as a novel cytoplasmic effector that differentiates between the retrograde and anterograde IFT complexes.
doi:10.1083/jcb.201204072
PMCID: PMC3392940  PMID: 22778277
23.  Role of Primary Cilia in Brain Development and Cancer 
Summary
The primary cilium, a hair-like extension from a cell’s surface, acts as a sensory organelle to receive signals that regulate cellular behavior and physiology. Like most mammalian cells, neural progenitors and neurons have primary cilia. Recent studies show that this tiny projection plays important roles in brain development and diseases. Ciliary mutant mice show defects in brain patterning, progenitor proliferation, and specification of adult neural stem cells. Primary cilia also have dual opposing functions in the development of brain tumors. Ciliary defects are associated with genetic syndromes that frequently have neurological symptoms. Understanding the multifaceted roles that primary cilia have in brain development will provide important insights into the mechanism of brain development and diseases.
doi:10.1016/j.conb.2009.12.002
PMCID: PMC2829308  PMID: 20080044
24.  Unique properties of Drosophila spermatocyte primary cilia 
Biology Open  2013;2(11):1137-1147.
Summary
The primary cilium is an essential organelle required for animal development and adult homeostasis that is found on most animal cells. The primary cilium contains a microtubule-based axoneme cytoskeleton that typically grows from the mother centriole in G0/G1 phase of the cell cycle as a membrane-bound compartment that protrudes from the cell surface. A unique system of bidirectional transport, intraflagellar transport (IFT), maintains the structure and function of cilia. While the axoneme is dynamic, growing and shrinking at its tip, at the same time it is very stable to the effects of microtubule-targeting drugs. The primary cilia found on Drosophila spermatocytes diverge from the general rules of primary cilium biology in several respects. Among these unique attributes, spermatocyte cilia assemble from all four centrioles in an IFT-independent manner in G2 phase, and persist continuously through two cell divisions. Here, we show that Drosophila spermatocyte primary cilia are extremely sensitive to microtubule-targeting drugs, unlike their mammalian counterparts. Spermatocyte cilia and their axonemes fail to assemble or be maintained upon nocodazole treatment, while centriole replication appears unperturbed. On the other hand, paclitaxel (Taxol), a microtubule-stabilizing drug, disrupted transition zone assembly and anchoring to the plasma membrane while causing spermatocyte primary cilia to grow extensively long during the assembly/elongation phase, but did not overtly affect the centrioles. However, once assembled to their mature length, spermatocyte cilia appeared unaffected by Taxol. The effects of these drugs on axoneme dynamics further demonstrate that spermatocyte primary cilia are endowed with unique assembly properties.
doi:10.1242/bio.20135355
PMCID: PMC3828760  PMID: 24244850
Drosophila; Centriole; Centrosome; Cilia; Spermatocyte; Transition zone
25.  Loss of primary cilia occurs early in breast cancer development 
Cilia  2014;3:7.
Background
Primary cilia are microtubule-based organelles that protrude from the cell surface. Primary cilia play a critical role in development and disease through regulation of signaling pathways including the Hedgehog pathway. Recent mouse models have also linked ciliary dysfunction to cancer. However, little is known about the role of primary cilia in breast cancer development. Primary cilia expression was characterized in cancer cells as well as their surrounding stromal cells from 86 breast cancer patients by counting cilia and measuring cilia length. In addition, we examined cilia expression in normal epithelial and stromal cells from reduction mammoplasties as well as histologically normal adjacent tissue for comparison.
Results
We observed a statistically significant decrease in the percentage of ciliated cells on both premalignant lesions as well as in invasive cancers. This loss of cilia does not correlate with increased proliferative index (Ki67-positive cells). However, we did detect rare ciliated cancer cells present in patients with invasive breast cancer and found that these express a marker of basaloid cancers that is associated with poor prognosis (Cytokeratin 5). Interestingly, the percentage of ciliated stromal cells associated with both premalignant and invasive cancers decreased when compared to stromal cells associated with normal tissue. To understand how cilia may be lost during cancer development we analyzed the expression of genes required for ciliogenesis and/or ciliary function and compared their expression in normal versus breast cancer samples. We found that expression of ciliary genes were frequently downregulated in human breast cancers.
Conclusions
These data suggest that primary cilia are lost early in breast cancer development on both the cancer cells and their surrounding stromal cells.
doi:10.1186/2046-2530-3-7
PMCID: PMC4076761  PMID: 24987519
Primary cilia; Invasive breast cancer; Carcinoma in situ; Cancer-associated stroma; Ciliogenesis; Cilia length

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