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.

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.

Polycystin-1 C terminus cleavage and its relation with polycystin-2, two proteins involved in polycystic kidney disease / Clivaje del C-terminal de policistina-1 y su relación con policistina-2, dos proteínas involucradas en la poliquistosis renal

Autosomal dominant polycystic kidney disease (ADPKD), a most common genetic cause of chronic renal failure, is characterized by the progressive development and enlargement of cysts in kidneys and other organs. The cystogenic process is highly complex and involves a high proliferative rate, increased apoptosis, altered protein sorting, changed secretory characteristics, and disorganization of the extracellular matrix. ADPKD is caused by mutations in the genes encoding polycystin-1 (PC-1) or polycystin-2 (PC-2). PC-1 undergoes multiple cleavages that intervene in several signaling pathways involved in cellular proliferation and differentiation mechanisms. One of these cleavages releases the cytoplasmic C-terminal tail of PC-1. In addition, the C-terminal cytoplasmic tails of PC-1 and PC-2 interact in vitro and in vivo. The purpose of this review is to summarize recent literature that suggests that PC-1 and PC-2 may function through a common signaling pathway necessary for normal tubulogenesis. We hope that a better understanding of PC-1 and PC-2 protein function will lead to progress in diagnosis and treatment for ADPKD.

La poliquistosis renal autosómica dominante (ADPKD por sus siglas en inglés) es una causa genética muy común de falla renal crónica que se caracteriza por el progresivo desarrollo y agrandamiento de quistes en los riñones y en otros órganos. El proceso de cistogénesis comprende incrementos en la proliferación y muerte celular por apoptosis, así como alteraciones en la distribución intracelular de proteínas, el movimiento transcelular de solutos y organización de la matriz extracelular. ADPKD es causada por mutaciones en los genes que codifican para policistina-1 (PC-1) o policistina-2 (PC-2). PC-1 puede sufrir múltiples clivajes y los fragmentos generados intervienen en diferentes cascadas de señalización involucradas en mecanismos de proliferación y diferenciación celular. Uno de estos clivajes libera el extremo C-terminal citoplasmático de la PC-1. Se ha demostrado que los extremos C-terminal citoplasmático de PC-1 y PC-2 pueden interactuar tanto in vitro como in vivo. El propósito de esta revisión es resumir la literatura más reciente que sugiere que PC-1 y PC-2 pueden funcionar a través de una cascada de señalización común necesaria para la tubulogénesis normal. Creemos que una mejor comprensión de los mecanismos moleculares de acción de PC-1 y PC-2 contribuirán al progreso en el diagnóstico y tratamiento de ADPKD.

The role of primary cilium in bone tissue mechanotransduction / 医用生物力学

Bone tissues constantly receive the mechanical stimulation and maintain the dynamic balance of bone formation and resorption. Currently, the mechanism of how bone tissues sense the mechanical stimulation is still unknown. An increasing number of studies have shown that primary cilium may be the mechanical sensor of bone tissues. The primary cilium maybe transfer the extracellular mechanical signals into intracellular biochemical message through them, and the mechanical stimulation received by bone tissues can regulate bone remodeling finally. This article reviews the current researches on primary cilium, predicts the research tendency and tries to lay some foundation for the use of primary cilium to prevent and treat osteoporosis.

Molecular and cellular pathogenesis of autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common human life-threatening monogenic disorders. The disease is characterized by bilateral, progressive renal cystogenesis and cyst and kidney enlargement, often leading to end-stage renal disease, and may include extrarenal manifestations. ADPKD is caused by mutation in one of two genes, PKD1 and PKD2, which encode polycystin-1 (PC1) and polycystin-2 (PC2), respectively. PC2 is a non-selective cation channel permeable to Ca2+, while PC1 is thought to function as a membrane receptor. The cyst cell phenotype includes increased proliferation and apoptosis, dedifferentiation, defective planar polarity, and a secretory pattern associated with extracellular matrix remodeling. The two-hit model for cyst formation has been recently extended by the demonstration that early gene inactivation leads to rapid and diffuse development of renal cysts, while inactivation in adult life is followed by focal and late cyst formation. Renal ischemia/reperfusion, however, can function as a third hit, triggering rapid cyst development in kidneys with Pkd1 inactivation induced in adult life. The PC1-PC2 complex behaves as a sensor in the primary cilium, mediating signal transduction via Ca2+ signaling. The intracellular Ca2+ homeostasis is impaired in ADPKD, being apparently responsible for the cAMP accumulation and abnormal cell proliferative response to cAMP. Activated mammalian target for rapamycin (mTOR) and cell cycle dysregulation are also significant features of PKD. Based on the identification of pathways altered in PKD, a large number of preclinical studies have been performed and are underway, providing a basis for clinical trials in ADPKD and helping the design of future trials.

Regulation of ciliary trafficking of polycystin-2 and the pathogenesis of autosomal dominant polycystic kidney disease / 中南大学学报(医学版)

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common human hereditary disorder characteristic of development of bilateral multiple fluid-filled kidney cysts. Accumulated evidence has suggested that primary cilium of renal epithelial cell plays a key role in cystogenesis. In this article we will give an overview on the basic information about polycystic kidney disease (PKD) and summarize the recent progresses in studies of regulation of polycystin-1 and -2 trafficking to cilia. We will also discuss the possible role of trafficking defects of polycystins on the pathogenesis of ADPKD.

Endophthalmitis Caused by an Intraocular Cilium

PURPOSE: To report a case of intraocular cilium revealed by diagnostic vitrectomy in a case of stubborn uveitis that was unresponsive to steroid therapy. CASE SUMMARY: A 39-year-old man was referred to our hospital due to decreased vision in his right eye that started two months prior to presentation. He had previously been treated for a diagnosis of iridocyclitis. The patient's history revealed a blunt trauma to the right eye while wearing glasses after which he developed a microhyphema and was treated for traumatic iritis at another clinic 3 months ago. He was treated with topical and oral steroids after being diagnosed with iridocyclitis and had recently been prescribed additional oral cyclosporine because his condition had not improved. Ocular examination revealed inflammatory cells in the anterior chamber and vitreous cavity with hand motion vision. Ultrasonography revealed a hazy vitreous cavity but the retina was flat. Diagnostic vitrectomy with intravitreal antibiotic injection was performed and an intraocular foreign body presumed as a cilium was detected without an entrance wound on the exterior or interior surface of the eye. After removal of the foreign body, the patient's vision was completely recovered. CONCLUSIONS: In cases of chronic uveitis that do not respond to immunosuppressive treatment without a clearly definable cause, diagnostic vitrectomy should be considered, keeping in mind the possibility of intraocular foreign body.

ULTRASTRUCTURE OF RESPIRATORY CILIA IN HUMAN / 解剖学报

The respiratory cilia of normal and abnormal regions in 20 patients with lung cancer or tuberculosis were observed under electron microscope.The results show that the 9?2+2 microtubules arrangement was seen in cross section of the cilium. Ultrastructure of the cilia is about the same as that of other mammalian ceils. However,a very interesting finding was that the ciliary rootlets became greatly hypertrophied.Thus,the structure was easily identified.It appeared as striated muscles. Therefore we propose a new idea that is quite different from Satir's hypothesis about the mechanism of ciliary movement.We think that ciliary rootlets may generate movement rather than fix cilia.Dynein arms and radial spoke may be involved in supporting and fixing for ciliary movement.