Primary cilia support cartilage regeneration after injury / 国际口腔科学杂志·英文版

In growing children, growth plate cartilage has limited self-repair ability upon fracture injury always leading to limb growth arrest. Interestingly, one type of fracture injuries within the growth plate achieve amazing self-healing, however, the mechanism is unclear. Using this type of fracture mouse model, we discovered the activation of Hedgehog (Hh) signaling in the injured growth plate, which could activate chondrocytes in growth plate and promote cartilage repair. Primary cilia are the central transduction mediator of Hh signaling. Notably, ciliary Hh-Smo-Gli signaling pathways were enriched in the growth plate during development. Moreover, chondrocytes in resting and proliferating zone were dynamically ciliated during growth plate repair. Furthermore, conditional deletion of the ciliary core gene Ift140 in cartilage disrupted cilia-mediated Hh signaling in growth plate. More importantly, activating ciliary Hh signaling by Smoothened agonist (SAG) significantly accelerated growth plate repair after injury. In sum, primary cilia mediate Hh signaling induced the activation of stem/progenitor chondrocytes and growth plate repair after fracture injury.

Clinical phenotypes of primary ciliary dyskinesia / 中南大学学报(医学版)

Primary ciliary dyskinesia (PCD) is a hereditary disease characterized by airway mucociliary clearance dysfunction. The estimated prevalence of PCD is 1꞉10 000 to 1꞉20 000. The main respiratory manifestations in children are cough, expectoration, chronic rhinitis, sinusitis, and chronic otitis media, while the most common symptoms in adults are chronic sinusitis, bronchiectasis, and infertility. About 50% of patients with certain PCD-related gene variants are combined with situs inversus, and the incidence of congenital heart disease is also high. The pathogenesis behind PCD is that gene variants cause structural or functional disorders of respiratory cilia and motile cilia of other organs, leading to a series of heterogeneous clinical manifestations, which makes it difficult to identify and diagnose PCD. Combining different disease screening tools and understanding the relationship between genotypes and phenotypes may facilitate early diagnosis and treatment for PCD.

The roles of intraflagellar transport (IFT) protein 25 in mammalian signaling transduction and flagellogenesis / 亚洲男科学杂志(英文版)

Cilium, an organelle with a unique proteome and organization, protruding from the cell surface, generally serves as a force generator and signaling compartment. During ciliogenesis, ciliary proteins are synthesized in cytoplasm and transported into cilia by intraflagellar transport (IFT) particles, where the inner counterparts undergo reverse trafficking. The homeostasis of IFT plays a key role in cilial structure assembly and signaling transduction. Much progress has been made on the mechanisms and functions of IFT; however, recent studies have revealed the involvement of IFT particle subunits in organogenesis and spermatogenesis. In this review, we discuss new concepts concerning the molecular functions of IFT protein IFT25 and how its interactions with other IFT particle subunits are involved in mammalian development and fertility.

Pathogenic genes and corresponding ciliary defects associated with primary ciliary dyskinesia / 中华医学遗传学杂志

Primary ciliary dyskinesia (PCD) is a recessive genetic disorder of motile cilia with substantial genetic and phenotypic heterogeneity. Clinical features of PCD vary from one patient to another, and no single test has the sensitivity and specificity to accurately diagnose PCD. Genetic testing combined with other auxiliary tests can facilitate the confirmatory diagnosis of PCD. So far more than 40 genes have been associated with PCD, but most research have focused on common genes, which hinders our understanding of other rare PCD-genes. This review has summarized the PCD-associated genes and the corresponding characteristics of dysfunctional cilia, with an aim to provide a basis for early identification of such diseases.

Cellular primary cilia and human diseases / 生理学报

Cellular primary cilium, located on the surface of virtually all mammalian cells, is a strictly conserved organelle which regulates cell biological process and maintains cell homeostasis by modulating cell proliferation, differentiation, migration, polarity, signal cascades and other life activities. Some diseases caused by mutations in genes encoding structural proteins or accessory proteins of primary cilia are collectively termed as "ciliopathies", which can occur in embryo, infancy and even adulthood. Ciliopathies not only involve a single organ, but also involve multiple organs and multiple systems, showing variable symptoms and overlapping symptoms. This review mainly summarizes the effects of ciliopathy-associated gene mutations on bone, tooth, skin, liver and bile duct, kidney, brain, retina, heart and other organs, uncovers their molecular mechanisms and provides some novel insights into therapy of ciliopathies.

Primary cilium and its role in tumorigenesis / 浙江大学学报·医学版

The primary cilium, a sensory organelle that protrudes from the surface of most eukaryotic cells, receives and transduces various critical signals that are essential for normal development and homeostasis. Structural or functional disruption of primary cilia causes a number of human diseases, including cancer. Primary cilia has cross talks with cell cycle and it may act as a cell cycle checkpoint to suppress cancer development. Moreover, primary cilia has cross-regulation with autophagy, which may affect tumor progression. We then discuss the association of the primary cilia with several oncogenic signaling pathways, including Shh, Wnt, Notch and platelet-derived growth factor receptor (PDGFR). Since these signaling pathways are often over-activated in many types of human cancers, primary cilia are likely to play a role in the tumorigenesis by modulating these pathways. Finally, we summarize current progress on the role of cilia during tumorigenesis and the challenges that the cilia-cancer field faces.

Primary cilia in hard tissue development and diseases / 医学前沿

Bone and teeth are hard tissues. Hard tissue diseases have a serious effect on human survival and quality of life. Primary cilia are protrusions on the surfaces of cells. As antennas, they are distributed on the membrane surfaces of almost all mammalian cell types and participate in the development of organs and the maintenance of homeostasis. Mutations in cilium-related genes result in a variety of developmental and even lethal diseases. Patients with multiple ciliary gene mutations present overt changes in the skeletal system, suggesting that primary cilia are involved in hard tissue development and reconstruction. Furthermore, primary cilia act as sensors of external stimuli and regulate bone homeostasis. Specifically, substances are trafficked through primary cilia by intraflagellar transport, which affects key signaling pathways during hard tissue development. In this review, we summarize the roles of primary cilia in long bone development and remodeling from two perspectives: primary cilia signaling and sensory mechanisms. In addition, the cilium-related diseases of hard tissue and the manifestations of mutant cilia in the skeleton and teeth are described. We believe that all the findings will help with the intervention and treatment of related hard tissue genetic diseases.

Case report of neurofibromatosis type 1 combined with primary ciliary dyskinesia / 医学前沿

Neurofibromatosis (NF) is a genetic disease in which the lungs are rarely involved. However, in NF cases with lung involvement, chest computed tomography may show bilateral basal reticulations, apical bullae, and cysts without bronchiectasis. Herein, we report a patient diagnosed with NF on the basis of the results of genetic testing who presented with early-onset wet cough and bronchiectasis. Considering the differential diagnosis of bronchiectasis combined with his early-onset wet cough, sinusitis, and sperm quality decline, we considered the possibility of primary ciliary dyskinesia (PCD). Further electron microscopy analysis of cilia and identification of homozygous mutations in the RSPH4A gene confirmed the diagnosis of PCD. Therefore, for patients with NF, when an image change exists in the lungs that does not correspond to NF, the possibility of other diagnoses, including PCD, must be considered.

Advances on the role of primary cilia in neurological diseases / 生理学报

Primary cilium, widely distributed in mammalian central nervous system, is an important extracellular organelle of cells. The primary cilia contain a variety of ion channels, G-protein coupled receptors and different kinds of kinases, which indicates that primary cilia can detect extracellular signals and transduce them into cells to regulate various cellular and physiological processes. In humans, mutations of genes related to structure and function of primary cilia always cause various monogenetic diseases. Moreover, a series of neuropsychiatric diseases and neurodevelopmental dysplasia are caused by abnormal functions of G-protein coupled receptors, kinases and ion channels in primary cilia. This article reviews recent research progress on the role of primary cilia in related neurological diseases.

Diagnóstico de la discinecia ciliar primaria / Diagnosis of the primary ciliary dyskinesia

Primary ciliary dyskinesia is a congenital disorder due to abnormal motile ciliary function, especially in the airway epithelium. The mucociliary clearance is impaired, producing reoccurring respiratory tract infections, usually resulting in bronchiectasis as an adult. Patients also have frequent ear and sinus infections and almost 50% of them have situs inversus. Diagnosis of primary ciliary dyskinesia is difficult because there is not a single gold standard test, resulting in the need of a multi-test approach. Until recently in our country we only had transmission electron microscopy, but nasal nitric oxide and high speed video microscopy are now available. In this article we will detail the most important clinical characteristics that make us suspect the presence of primary ciliary dyskinesia at different ages and the methods available for its diagnosis.

La discinesia ciliar primaria es una enfermedad congénita debida a una alteración del movimiento normal de los cilios, especialmente a nivel del epitelio respiratorio. Esto se traduce en una alteración del clearance mucociliar lo que predispone al paciente a tener infecciones respiratorias repetidas, terminando en la aparición de bronquiectasias en la edad adulta. También son frecuentes las infecciones repetidas de oídos y cavidades perinasales. La presencia de situs inverso puede verse en hasta en 50% de los pacientes con esta enfermedad. El diagnóstico de discinesia ciliar primaria es difícil ya que no existe un examen que sea considerado patrón de oro, por lo que se requiere la realización de distintos exámenes. En nuestro país hasta hace poco tiempo solo contábamos con la microscopía electrónica, pero recientemente se ha sumado la medición de óxido nítrico nasal y la videomicroscopía de alta velocidad. En el presente artículo se detallarán las características clínicas más importantes que hacen sospechar la presencia de DCP en las distintas edades y los métodos disponibles para su diagnóstico.

Interplay Between Primary Cilia and Autophagy and Its Controversial Roles in Cancer

Primary cilia and autophagy are two distinct nutrient-sensing machineries required for maintaining intracellular energy homeostasis, either via signal transduction or recycling of macromolecules from cargo breakdown, respectively. Potential correlations between primary cilia and autophagy have been recently suggested and their relationship may increase our understanding of the pathogenesis of human diseases, including ciliopathies and cancer. In this review, we cover the current issues concerning the bidirectional interaction between primary cilia and autophagy and discuss its role in cancer with cilia defect.

A novel compound heterozygous mutation in DNAH5 in a Korean neonate with primary ciliary dyskinesia

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disease affecting motile cilia. A female neonate was hospitalized with respiratory distress 72 hours after birth and showed concurrent situs inversus. She was identified to have compound heterozygous mutations in DNAH5: c.5647C>T, p.Arg1883Ter (nonsense mutation) and c.10810dupA, p.Ile3604AsnfsTer2 (frameshift mutation). Sanger sequencing confirmed that they were inherited from her father and mother, respectively, and she was diagnosed with PCD. The c.10810dupA is a novel DNAH5 mutation that has never been reported. To the best of our knowledge, this is the first report describing DNAH5 mutations in a Korean patient with PCD.

Bardet-Biedl syndrome protein-8 is involved in flagellar membrane protein transport in Chlamydomonas reinhardtii / 生物工程学报

Cilia and flagella on eukaryotic cells are polarized organelles extending from the surfaces of cells, which participate not only in cell motility, but also in signal transduction and other processes. Structural or functional abnormalities of cilia can cause various human diseases, termed ciliopathies. Bardet-Biedl syndrome (BBS) is a ciliopathic human genetic disorder, and the pathogenesis is that mutated BBS genes result in abnormal cilia function. In order to study the pathogenic genes BBS8, we screened bbs8 mutant in Chlamydomonas reinhardtii and did a lot of physiology and biochemistry experiments. We affirmed that BBS8 protein was a cilia protein and had specific localization in the basal body by immunofluorescence (IF). The bbs8 mutant lost photokinesis, and it was defective in flagella shortening with drug induction. The results of silver staining and mass spectrometric analysis showed aberrant accumulation of flagellar proteins in the mutant flagella. We concluded that the BBS8 protein plays a significant role in flagellar membrane proteins transport, and the BBS8 protein might mediate retrograde transport to exert physiological function in the process.

Long-term Outcome of Incision and Curettage Treatment in Patients with Lacrimal Gland Ductulitis

PURPOSE: To describe the effects and long-term outcomes of incision and curettage treatment in patients with lacrimal gland ductulitis.METHODS: Twenty-four patients (24 eyes) with lacrimal gland ductulitis who were treated at Saevit Eye Hospital from June 2010 to November 2016. All patients underwent incision and curettage through the lacrimal ductule, and granules or concretions were removed. After the procedure, oral and topical antibiotics, oral anti-inflammatory agent were used for a week. Clinical presentations of the patients were analyzed. The resolution of symptoms and inflammatory signs and recurrence were evaluated more than 12 months after the procedure including telephone follow-up by a specialist nurse.RESULTS: Common symptoms were a painful, swelling mass with mucous discharge (17 eyes) and conjunctival injection (7 eyes) at the lateral canthal area. During the procedure, 22 patients (91.7%) had typical sulfur granule of Actinomyces, and 10 patients (41.7%) had many cilia in the expressed debris from the ductule. Twenty-three of 24 patients had resolution of symptoms after the procedure and all but one patient (95.8%) showed no recurrence.CONCLUSIONS: Incision and curettage is a simple and less invasive procedure that may be considered as a first treatment option for lacrimal gland ductulitis. Furthermore, incision and curettage of the affected lacrimal ductule has been shown to be effective at minimizing long-term recurrence of lacrimal ductulitis.

Pulsed electromagnetic fields stimulating osteogenic differentiation and maturation involves primary cilia-PI3K/AKT pathway / 北京大学学报(医学版)

OBJECTIVE@#To study whether the pulsed electromagnetic fields (PEMF) promoting rat osteoblasts differentiation and maturation is related to the primary cilia and PI3K/AKT pathway, and to explore the mechanism of PEMF in promoting bone differentiation.@*METHODS@#Enzyme solution was used to obtain newborn SD rats calvarial osteoblasts (ROB), which were processed by 50 Hz 0.6 mT PEMF for 0, 0.5, 1, 1.5 and 2 h, detecting PI3K and AKT protein expression and changes in primary cilia length and incidence; with LY294002 blocking PI3K/AKT signaling pathways we observed whether PEMF promoted osteogenic differentiation of ROB was affected; by interfering IFT88 gene expression by RNAi to inhibit primary cilia we observed whether PI3K/AKT signaling pathway and osteogenic differentiation of ROB was affected. Osteogenic differentiation indexes included alkaline phosphatase (ALP) activity, Real-time PCR and Western blot detection of osteogenic related genes of BMP-2, COL-1 and OSX and calcified nodules number, etc..@*RESULTS@#After exposure to PEMF for 0, 0.5, 1, 1.5, and 2 h, the protein expression of PI3K and AKT in ROB were increased significantly (P<0.01) and the primary cilia became longer; and the protein expression of PI3K reached the highest level at 0.5 h, as the treatment time of PEMF increased, the PI3K protein expression decreased. AKT showed higher protein expression at 0.5 h and 1.5 h. After blocking the PI3K/AKT signaling pathway with the PI3K blocker LY294002, PEMF could no longer increase ALP activity and the gene expressions of BMP-2, COL-1, OSX which were osteogenically related. However, PEMF could increase the ALP activity and the osteogenically related gene expression in ROB before blocking. After RNAi interfered the primary cilia, PEMF could no longer increase the protein expression of PI3K, which indicated that PEMF could not activate the PI3K/AKT signaling pathway after primary cilia interfering; secondly, the effect of PEMF on enhancing ALP activity disappeared, it also decrease the gene expressions of BMP-2, COL-1, and OSX, and the ability of increasing the calcification nodule formation also disappeared, indicating that the ability of PEMF to promote osteoblast maturation and mineralization disappeared after primary cilia interference.@*CONCLUSION@#PEMF activated the PI3K/AKT signaling pathway through primary cilia on the surface of osteoblasts, then promoted bone formation activity and differentiation.

The First Case of Diarrhoea in Tibetan Sheep, Ovis aries, Caused by Balantidium coli in the Qinghai Tibetan Plateau Area, China

This study was carried out to determine the pathogen-causing diarrhoea in sheep Ovis aries in the Qinghai Tibetan Plateau Area, China. A trophozoite was identified as species of ciliate alveolates infecting the sheep based on morphological characteristics examined by microscope. It was mostly spherical, colourless and transparent, with many vesicles. Macronucleus and contractile vacuoles could not be distinguished. Size of the trophozoite was 80–180×70–150 μm and its surface was covered with cilia. Molecular analysis based on sequences of 18S rRNA and ITS genes confirmed the ciliate species as Balantidium coli. According to the literature, there have been many epidemiological investigations of B. coli infection in pigs, monkeys and humans. To our knowledge, this was the first report of B. coli infections in sheep in the Qinghai Tibetan Plateau Area of China, or eleswhere around the world. Importantly, the sheep case was rare but raised our concern that B. coli may spread across species and expand its host range.

Repeated restraint stress promotes hippocampal neuronal cell ciliogenesis and proliferation in mice / 한국실험동물학회지

Stress severely disturbs physiological and mental homeostasis which includes adult neurogenesis in hippocampus. Neurogenesis in hippocampus is a key feature to adapt to environmental changes and highly regulated by multiple cellular signaling pathways. The primary cilium is a cellular organelle, which acts as a signaling center during development and neurogenesis in adult mice. However, it is not clear how the primary cilia are involved in the process of restraint (RST) stress response. Using a mouse model, we examined the role of primary cilia in repeated and acute RST stress response. Interestingly, RST stress increased the number of ciliated cells in the adult hippocampal dentate gyrus (DG). In our RST model, cell proliferation in the DG also increased in a time-dependent manner. Moreover, the analysis of ciliated cells in the hippocampal DG with cell type markers indicated that cells that were ciliated in response to acute RST stress are neurons. Taken together, these findings suggest that RST stress response is closely associated with an increase in the number of ciliated neurons and leads to an increase in cell proliferation.

Primary Cilia as a Signaling Platform for Control of Energy Metabolism

Obesity has become a common healthcare problem worldwide. Cilia are tiny hair-like organelles on the cell surface that are generated and anchored by the basal body. Non-motile primary cilia have been considered to be evolutionary rudiments until a few decades, but they are now considered as important signaling organelles because many receptors, channels, and signaling molecules are highly expressed in primary cilia. A potential role of primary cilia in metabolic regulation and body weight maintenance has been suspected based on rare genetic disorders termed as ciliopathy, such as Bardet-Biedl syndrome and Alström syndrome, which manifest as obesity. Recent studies have demonstrated involvement of cilia-related cellular signaling pathways in transducing metabolic information in hypothalamic neurons and in determining cellular fate during adipose tissue development. In this review, we summarize the current knowledge about cilia and cilia-associated signaling pathways in the regulation of body metabolism.

Kartagener syndrome, current data on a classical disease. case report

ABSTRACT Introduction: This article addresses the general aspects (pathophysiology, embryology, clinical presentation and prognosis) of the Kartagener syndrome (KS). Case presentation: 26-year-old male patient, with a history of complicated sinusitis with cerebral abscess and secondary epilepsy, who consulted to the Hospital Universitario Nacional de Colombia due to headache, fever and mucus expectoration. The presence of situs inversus, chronic sinusitis and bronchiectasis suggested a diagnosis of primary ciliary dyskinesia and KS. Discussion: Differential diagnoses of KS should be framed in its possible causal relationship with primary ciliary dyskinesia and other diagnoses associated with secondary ciliary dysfunction, such as cystic fibrosis, immunodeficiency and anatomical-functional conditions with rhinosenopulmonary involvement. Clinical suspicion of KS occurs when the heart is auscultated on the right and the liver is palpated on the left. Confirmation is achieved through imaging methods that prove visceral heterotaxia, indirect methods related to scan of ciliary malfunction (nasal nitric oxide, video microscopy) and ciliary biopsy that demonstrates the defect of the ciliary ultrastructure. Conclusions: Respiratory infectious involvement in patients with KS is explained by the alteration of the cilia, which leads both to the malposition of some organs and to the structural and functional alteration of others.

RESUMEN Introducción. El presente artículo aborda los aspectos generales (fisiopatología, embriología, presentación clínica y pronóstico) del síndrome de Kartagener (SK). Presentación del caso. Paciente masculino de 26 años, con antecedente de sinusitis complicada con absceso cerebral y epilepsia secundaria, quien consulta al Hospital Universitario Nacional de Colombia por cefalea, fiebre y expectoración mucosa. La presencia de situs inverso, sinusitis crónica y bronquiectasias sugieren diagnóstico de discinesia ciliar primaria y SK. Discusión. Los diagnósticos diferenciales del SK deben enmarcarse en la relación de causalidad posible con la discinesia ciliar primaria y de otros diagnósticos asociados a disfunción ciliar secundaria como fibrosis quística, inmunodeficiencia y condiciones anatómicas-funcionales con compromiso rinosenopulmonar. La sospecha clínica del SK se da cuando se ausculta el corazón a la derecha y se palpa el hígado a la izquierda. Su confirmación es mediante métodos de imagen que comprueban la heterotaxia visceral, por métodos indirectos de mal funcionamiento del barrido ciliar (óxido nítrico nasal, video microscopia) y por biopsia ciliar que demuestra el defecto de la ultraestructura ciliar. Conclusiones. El compromiso infeccioso respiratorio presentado por los pacientes que cursan con SK se explica por la alteración en la cilia, que conlleva tanto a la malposición de algunos órganos como a la alteración estructural y funcional de otros.

Can Tissue Cilia Lengths and Urine Cilia Proteins Be Markers of Kidney Diseases? / 전남의대학술지

The primary cilium is an organelle which consists of a microtubule in the core and a surrounding cilia membrane, and has long been recognized as a “vestigial organelle”. However, new evidence demonstrates that the primary cilium has a notable effect on signal transduction in the cell and is associated with some genetic and non-genetic diseases. In the kidney, the primary cilium protrudes into the Bowman's space and the tubular lumen from the apical side of epithelial cells. The length of primary cilia is dynamically altered during the normal cell cycle, being shortened by retraction into the cell body at the entry of cell division and elongated at differentiation. Furthermore, the length of primary cilia is also dynamically changed in the cells, as a result and/or cause, during the progression of various kidney diseases including acute kidney injury and chronic kidney disease. Notably, recent data has demonstrated that the shortening of the primary cilium in the cell is associated with fragmentation, apart from retraction into the cell body, in the progression of diseases and that the fragmented primary cilia are released into the urine. This data reveals that the alteration of primary cilia length could be related to the progression of diseases. This review will consider if primary cilia length alteration is associated with the progression of kidney diseases and if the length of tissue primary cilia and the presence or increase of cilia proteins in the urine is indicative of kidney diseases.