Role of Primary Cilia in Bone and Cartilage

The primary cilium is a nonmotile microtubule-based organelle in most vertebrate cell types. The primary cilium plays a critical role in tissue development and homeostasis by sensing and transducing various signaling pathways. Ciliary proteins such as intraflagellar transport (IFT) proteins as well as ciliary motor proteins, kinesin and dynein, comprise a bidirectional intraflagellar transport system needed for cilia formation and function. Mutations in ciliary proteins that lead to loss or dysfunction of primary cilia cause ciliopathies such as Jeune syndrome and Ellis–van Creveld syndrome and cause abnormalities in tooth development. These diseases exhibit severe skeletal and craniofacial dysplasia, highlighting the significance of primary cilia in skeletal development. Cilia are necessary for the propagation of hedgehog, transforming growth factor β, platelet-derived growth factor, and fibroblast growth factor signaling during osteogenesis and chondrogenesis. Ablation of ciliary proteins such as IFT80 or IFT20 blocks cilia formation, which inhibits osteoblast differentiation, osteoblast polarity, and alignment and reduces bone formation. Similarly, cilia facilitate chondrocyte differentiation and production of a cartilage matrix. Cilia also play a key role in mechanosensing and are needed for increased bone formation in response to mechanical forces.

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Swift Is a Novel BRCT Domain Coactivator of Smad2 in Transforming Growth Factor β Signaling

Molecular and Cellular Biology ◽

10.1128/mcb.21.12.3901-3912.2001 ◽

2001 ◽

Vol 21 (12) ◽

pp. 3901-3912 ◽

Cited By ~ 35

Author(s):

Kazuya Shimizu ◽

Pierre-Yves Bourillot ◽

Søren J. Nielsen ◽

Aaron M. Zorn ◽

J. B. Gurdon

Keyword(s):

Growth Factor ◽

Gene Transcription ◽

Target Genes ◽

Transforming Growth Factor ◽

Critical Role ◽

Gene Activation ◽

Transforming Growth Factor Β ◽

Growth Factor Signaling ◽

Dependent Manner ◽

Tgfβ Signaling

ABSTRACT Transforming growth factor β (TGFβ) signaling is transduced via Smad2–Smad4–DNA-binding protein complexes which bind to responsive elements in the promoters of target genes. However, the mechanism of how the complexes activate the target genes is unclear. Here we identify Xenopus Swift, a novel nuclear BRCT (BRCA1 C-terminal) domain protein that physically interacts with Smad2 via its BRCT domains. We examine the activity of Swift in relation to gene activation in Xenopus embryos. Swift mRNA has an expression pattern similar to that of Smad2. Swift has intrinsic transactivation activity and activates target gene transcription in a TGFβ-Smad2-dependent manner. Inhibition of Swift activity results in the suppression of TGFβ-induced gene transcription and defective mesendoderm development. Blocking Swift function affects neither bone morphogenic protein nor fibroblast growth factor signaling during early development. We conclude that Swift is a novel coactivator of Smad2 and that Swift has a critical role in embryonic TGFβ-induced gene transcription. Our results suggest that Swift may be a general component of TGFβ signaling.

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Dlec1 is required for spermatogenesis and male fertility in mice

Scientific Reports ◽

10.1038/s41598-020-75957-y ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Yu Okitsu ◽

Mamoru Nagano ◽

Takahiro Yamagata ◽

Chizuru Ito ◽

Kiyotaka Toshimori ◽

...

Keyword(s):

Male Fertility ◽

Primary Cilia ◽

Critical Role ◽

Intraflagellar Transport ◽

Suppressor Gene ◽

Tumour Suppressor Gene ◽

Adenocarcinoma Cells ◽

Cilia Formation ◽

Ring Complex

Abstract Deleted in lung and esophageal cancer 1 (DLEC1) is a tumour suppressor gene that is downregulated in various cancers in humans; however, the physiological and molecular functions of DLEC1 are still unclear. This study investigated the critical role of Dlec1 in spermatogenesis and male fertility in mice. Dlec1 was significantly expressed in testes, with dominant expression in germ cells. We disrupted Dlec1 in mice and analysed its function in spermatogenesis and male fertility. Dlec1 deletion caused male infertility due to impaired spermatogenesis. Spermatogenesis progressed normally to step 8 spermatids in Dlec1−/− mice, but in elongating spermatids, we observed head deformation, a shortened tail, and abnormal manchette organization. These phenotypes were similar to those of various intraflagellar transport (IFT)-associated gene-deficient sperm. In addition, DLEC1 interacted with tailless complex polypeptide 1 ring complex (TRiC) and Bardet–Biedl Syndrome (BBS) protein complex subunits, as well as α- and β-tubulin. DLEC1 expression also enhanced primary cilia formation and cilia length in A549 lung adenocarcinoma cells. These findings suggest that DLEC1 is a possible regulator of IFT and plays an essential role in sperm head and tail formation in mice.

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Role of Primary Cilia in Odontogenesis

Journal of Dental Research ◽

10.1177/0022034517713688 ◽

2017 ◽

Vol 96 (9) ◽

pp. 965-974 ◽

Cited By ~ 6

Author(s):

M. Hampl ◽

P. Cela ◽

H.L. Szabo-Rogers ◽

M. Kunova Bosakova ◽

H. Dosedelova ◽

...

Keyword(s):

Signaling Pathways ◽

Primary Cilium ◽

Mammalian Cells ◽

Primary Cilia ◽

Tooth Development ◽

Critical Role ◽

Current Evidence ◽

Developmental Defects ◽

Dental Tissues ◽

The Impact

Primary cilium is a solitary organelle that emanates from the surface of most postmitotic mammalian cells and serves as a sensory organelle, transmitting the mechanical and chemical cues to the cell. Primary cilia are key coordinators of various signaling pathways during development and maintenance of tissue homeostasis. The emerging evidence implicates primary cilia function in tooth development. Primary cilia are located in the dental epithelium and mesenchyme at early stages of tooth development and later during cell differentiation and production of hard tissues. The cilia are present when interactions between both the epithelium and mesenchyme are required for normal morphogenesis. As the primary cilium coordinates several signaling pathways essential for odontogenesis, ciliary defects can interrupt the latter process. Genetic or experimental alterations of cilia function lead to various developmental defects, including supernumerary or missing teeth, enamel and dentin hypoplasia, or teeth crowding. Moreover, dental phenotypes are observed in ciliopathies, including Bardet-Biedl syndrome, Ellis-van Creveld syndrome, Weyers acrofacial dysostosis, cranioectodermal dysplasia, and oral-facial-digital syndrome, altogether demonstrating that primary cilia play a critical role in regulation of both the early odontogenesis and later differentiation of hard tissue–producing cells. Here, we summarize the current evidence for the localization of primary cilia in dental tissues and the impact of disrupted cilia signaling on tooth development in ciliopathies.

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Primary Cilia in Trophoblastic Cells

Hypertension ◽

10.1161/hypertensionaha.120.15433 ◽

2020 ◽

Vol 76 (5) ◽

pp. 1491-1505

Author(s):

Andreas Ritter ◽

Susanne Roth ◽

Nina-Naomi Kreis ◽

Alexandra Friemel ◽

Samira Catharina Hoock ◽

...

Keyword(s):

Growth Factor ◽

Cell Lines ◽

Primary Cilium ◽

Primary Cilia ◽

Molecular Mechanisms ◽

Intraflagellar Transport ◽

First Trimester ◽

Tube Formation ◽

Trophoblastic Cell ◽

Trophoblastic Cells

The pathogenesis of preeclampsia, a pregnancy-related disease, is not completely understood. The primary cilium transduces a diverse array of signaling pathways important for vital cellular activities. Primary cilia were reported to facilitate trophoblastic cell invasion. We hypothesized their further functions in trophoblasts and were interested in related molecular mechanisms. We systematically examined the presence, length and percentage of the primary cilium, its mediated signal transduction, and its connection to trophoblast function. Various cellular and molecular methods were used including immunofluorescence staining, spheroid formation, gene analysis, invasion and tube formation assays with trophoblastic cell lines, primary trophoblasts, and placental tissues. We show that primary cilia are present in various trophoblastic cell lines derived from first trimester placentas. Cilia are also observable in primary trophoblasts, though in a small quantity. Importantly, primary cilia are shortened in trophoblastic cells derived from preeclamptic placentas. Mechanistically, interleukin-6, tumor necrosis factor-α or sera from patients with preeclampsia are able to reduce the length of primary cilia and impair the important sonic hedgehog signaling pathway. Functionally, trophoblastic cells with defective cilia display severe failures in their key functions, like migration, invasion and tube formation, also observed in trophoblastic cells depleted of the intraflagellar transport protein 88. This is accompanied by reduced gene expression of matrix metallopeptidases, vascular endothelial growth factor, and placental growth factor. This work highlights the significance of primary cilia in the functions of trophoblastic cells. Dysfunctional cilia may lead to compromised migration, invasion, and endothelial remodeling of trophoblastic cells, contributing to the development of preeclampsia.

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Exogenous Transforming Growth Factor-β in Brain-Induced Symptoms of Central Fatigue and Suppressed Dopamine Production in Mice

International Journal of Molecular Sciences ◽

10.3390/ijms22052580 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2580

Author(s):

Won Kil Lee ◽

Yeongyeong Kim ◽

Heejin Jang ◽

Joo Hye Sim ◽

Hye Jin Choi ◽

...

Keyword(s):

Growth Factor ◽

Transforming Growth Factor ◽

Neuroblastoma Cell ◽

Critical Role ◽

Central Fatigue ◽

Chronic Fatigue ◽

Human Neuroblastoma Cell ◽

Human Neuroblastoma ◽

Intracranial Injection ◽

Tgf Β1

Myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) is one of the most refractory diseases in humans and is characterized by severe central fatigue accompanied with various symptoms that affect daily life, such as impaired memory, depression, and somatic pain. However, the etiology and pathophysiological mechanisms of CFS remain unknown. To investigate the pathophysiological role of transforming growth factor (TGF)-β1, we injected a cytokine into the lateral ventricle of a C57BL/6 mouse. The intracranial injection of TGF-β1 increased the immobility duration in a forced swimming test (FST) and time spent at the closed arm in elevated plus maze (EPM) analysis. The mice injected with TGF-β1 into their brain showed increased sensitivity to pain in a von Frey test, and had a decreased retention time on rotarod and latency time in a bright box in a passive avoidance test. In addition, the serum levels of muscle fatigue biomarkers, lactate dehydrogenase (LDH) and creatine kinase (CK), were significantly increased after administration of TGF-β1. Intracranial injection of TGF-β1 significantly reduced the production of tyrosine hydroxylase (TH) in the ventral tegmental area, accompanied by a decreased level of dopamine in the striatum. The suppression of TH expression by TGF-β1 was confirmed in the human neuroblastoma cell line, SH-SY5Y. These results, which show that TGF-β1 induced fatigue-like behaviors by suppressing dopamine production, suggest that TGF-β1 plays a critical role in the development of central fatigue and is, therefore, a potential therapeutic target of the disease.

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Semaphorin 7A plays a critical role in TGF-β1–induced pulmonary fibrosis

Journal of Experimental Medicine ◽

10.1084/jem.20061273 ◽

2007 ◽

Vol 204 (5) ◽

pp. 1083-1093 ◽

Cited By ~ 118

Author(s):

Hye-Ryun Kang ◽

Chun Geun Lee ◽

Robert J. Homer ◽

Jack A. Elias

Keyword(s):

Growth Factor ◽

Pulmonary Fibrosis ◽

Transforming Growth Factor ◽

Critical Role ◽

Matrix Proteins ◽

Ccn Proteins ◽

Phosphatidylinositol 3 Kinase ◽

Smad 3 ◽

Dependent Pathway ◽

Tgf Β1

Semaphorin (SEMA) 7A regulates neuronal and immune function. In these studies, we tested the hypothesis that SEMA 7A is also a critical regulator of tissue remodeling. These studies demonstrate that SEMA 7A and its receptors, plexin C1 and β1 integrins, are stimulated by transforming growth factor (TGF)-β1 in the murine lung. They also demonstrate that SEMA 7A plays a critical role in TGF-β1–induced fibrosis, myofibroblast hyperplasia, alveolar remodeling, and apoptosis. TGF-β1 stimulated SEMA 7A via a largely Smad 3–independent mechanism and stimulated SEMA 7A receptors, matrix proteins, CCN proteins, fibroblast growth factor 2, interleukin 13 receptor components, proteases, antiprotease, and apoptosis regulators via Smad 2/3–independent and SEMA 7A–dependent mechanisms. SEMA 7A also played an important role in the pathogenesis of bleomycin-induced pulmonary fibrosis. TGF-β1 and bleomycin also activated phosphatidylinositol 3-kinase (PI3K) and protein kinase B (PKB)/AKT via SEMA 7A–dependent mechanisms, and PKB/AKT inhibition diminished TGF-β1–induced fibrosis. These observations demonstrate that SEMA 7A and its receptors are induced by TGF-β1 and that SEMA 7A plays a central role in a PI3K/PKB/AKT-dependent pathway that contributes to TGF-β1–induced fibrosis and remodeling. They also demonstrate that the effects of SEMA 7A are not specific for transgenic TGF-β1, highlighting the importance of these findings for other fibrotic stimuli.

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