The Roles of Primary cilia in Polycystic Kidney Disease

Kathem, Sarmed H.; Mohieldin, Ashraf M.; Nauli, Surya M.

doi:10.3934/molsci.2013.1.27

Cited by 48 publications

(36 citation statements)

References 108 publications

(137 reference statements)

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“…First observed by Kowalevsky in 1867 primary cilia were mostly ignored for the next 100 years . However, over the last 20–30 years a growing interest in their behavior has led to the discovery of their role in autosomal dominant polycystic kidney disease (ADPKD) and an increasing range of so called ciliopathies …”

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confidence: 99%

Zonal variation in primary cilia elongation correlates with localized biomechanical degradation in stress deprived tendon

Rowson

Knight

Screen

2016

Journal Orthopaedic Research

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Tenocytes express primary cilia, which elongate when tendon is maintained in the absence of biomechanical load. Previous work indicates differences in the morphology and metabolism of the tenocytes in the tendon fascicular matrix (FM) and the inter‐fascicular matrix (IFM). This study tests the hypothesis that primary cilia in these two regions respond differently to stress deprivation and that this is associated with differences in the biomechanical degradation of the extracellular matrix. Rat tail tendon fascicles were examined over a 7‐day period of either stress deprivation or static load. Seven days of stress deprivation induced cilia elongation in both regions. However, elongation was greater in the IFM compared to the FM. Stress deprivation also induced a loss of biomechanical integrity, primarily in the IFM. Static loading reduced both the biomechanical degradation and cilia elongation. The different responses to stress deprivation in the two tendon regions are likely to be important for the aetiology of tendinopathy. Furthermore, these data suggest that primary cilia elongate in response to biomechanical degradation rather than simply the removal of load. This response to degradation is likely to have important consequences for cilia signalling in tendon and as well as in other connective tissues. © 2016 The Authors. Journal of Orthopaedic Research Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 34:2146–2153, 2016.

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confidence: 99%

Zonal variation in primary cilia elongation correlates with localized biomechanical degradation in stress deprived tendon

Rowson

Knight

Screen

2016

Journal Orthopaedic Research

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“…56 The primary cilia of the collecting duct epithelium function as transmitters of mechano-and chemosensory stimuli to signaling pathways that regulate multiple key cellular processes including differentiation, proliferation, apoptosis, tissue homeostasis and cell polarity. 57 We have previously demonstrated that cystin, with two functional nuclear localization signals, can be released from the ciliary membrane through a myristoyl-electrostatic switch and translocate to the nucleus where it forms a regulatory complex with necdin to modulate Myc expression. 24 The Myc proto-oncogene plays a critical role in normal kidney development 58 and several lines of evidence suggest a central role for dysregulated Myc expression in the pathophysiology of polycystic kidney disease.…”

Section: Discussionmentioning

confidence: 99%

Cystin gene mutations cause autosomal recessive polycystic kidney disease associated with alteredMycexpression

Yang¹,

O’Connor²,

Kesterson

et al. 2020

Preprint

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Mutation of the Cys1 gene underlies the renal cystic disease in the Cys1 cpk/cpk (cpk) mouse that phenocopies human autosomal recessive polycystic kidney disease (ARPKD). Cystin, the protein product of Cys1, is expressed in the primary apical cilia of renal ductal epithelial cells. In previous studies, we showed that cystin regulates Myc expression via interaction with the tumor suppressor, necdin. Here, we demonstrate rescue of the cpk renal phenotype by kidney-specific expression of a cystin-GFP fusion protein encoded by a transgene integrated into the Rosa26 locus. In addition, we show that expression of the cystin-GFP fusion protein in collecting duct cells downregulates expression of Myc in cpk kidneys. Finally, we report the first human patient with an ARPKD phenotype due to homozygosity for a predicted deleterious splicing defect in CYS1.These findings suggest that mutations in the Cys1 mouse and CYS1 human orthologues cause an ARPKD phenotype that is driven by overexpression of the Myc proto-oncogene. Translational Statement:The cystin-deficient cpk mouse is a model for the study of autosomal recessive polycystic kidney disease (ARPKD). We show that the cpk mouse phenotype is associated with altered Myc expression. To date, the clinical relevance of cystin deficiency to human disease was unclear, due to the absence of ARPKD cases associated with CYS1 mutations. We report the first case of ARPKD linked to a CYS1 mutation disrupting normal splicing. These findings confirm the relevance of cystin deficiency to human ARPKD, implicate Myc in disease initiation or progression, and validate the cpk mouse as a translationally relevant disease model.

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“…They also act as flow and chemosensors, for example, in the collecting ducts of renal epithelia, where they project into the lumen of the duct and sense bulk filtrate physicochemical properties and flow 28,29 . When these primary cilia are defective, cell growth and proliferation become unregulated, resulting in one of the many possible ciliopathies 4,5 known as polycystic kidney disease 30,31 .…”

Section: Introductionmentioning

confidence: 99%

The molecular structure of primary cilia revealed by cryo-electron tomography

Kiesel

Viar

Tsoy

et al. 2020

Preprint

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Primary cilia are microtubule-based organelles involved in key signaling and sensing processes in eukaryotic cells. Unlike motile cilia, which have been thoroughly studied, the structure and the composition of primary cilia remain largely unexplored despite their fundamental role in development and homeostasis. They have for long been falsely regarded as simplified versions of motile cilia because they lack distinctive elements such as dynein arms, radial spokes, and central pair complex. However, revealing the detailed molecular composition and 3D structure of primary cilia is necessary in order to understand the mechanisms that govern their functions. Such structural investigations are so far being precluded by the challenging preparation of primary cilia for cryo-electron microscopy. Here, we developed an enabling method for investigating the structure of primary cilia at molecular resolution by cryo-electron tomography. We show that the well-known "9+0" arrangement of microtubule doublets is present only at the base of the primary cilium. A few microns away from the base the ciliary architecture changes into an unstructured bundle of EB1-decorated microtubule singlets and some actin filaments. Our results suggest the existence of a previously unobserved crosstalk between actin filaments and microtubules in the primary cilium. Our work provides unprecedented insights into the molecular structure of primary cilia and a general framework for uncovering their molecular composition and function in health and disease. This opens up new possibilities to study aspects of this important organelle that have so far been out of reach.We would like to thank the Electron Microscopy Facility (in particular Tobias Fürstenhaupt, Weihua Leng, Michaela Wilsch-Bräuninger) and the Light Microscope Facility from the Services and Facilities of the MPI-CBG for their support. We are thankful to Helin Rägel and Cécilie Martin-Lemaitre for their tips on MDCKII cell culture, Noreen Walker for the Imaris tutorial, and Tim-Oliver Buchholz for denoising cryo-tomography data. We thank Pavel Tomancak, Florian Jug, Dennis Diener, and Jan Brugues for the fruitful discussions and suggestions to the manuscript. We thank Oscar Gonzales for IT support. . developed the cryo-peel-off method, prepared samples for FM and EM imaging, acquired and reconstructed room temperature and cryo-tomograms, contributed to FM data acquisition, analysed EM and FM data, prepared figures, interpreted results, and contributed to writing and revising the manuscript. G.A.V. prepared samples and contributed to data acquisition of the room temperature tomography, analyzed cryo-EM data with subtomogram averaging and tomogram segmentation, analysed EM and FM data, prepared figures, interpreted results, and contributed to writing and revising the manuscript. N.T. analyzed cryo-ET data to average the microtubule singlets, contributed to supplementary figure preparation, contributed to the interpretation of data, and contributed to writing and revising the manuscript. R.M. pre...

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The Roles of Primary cilia in Polycystic Kidney Disease

Cited by 48 publications

References 108 publications

Zonal variation in primary cilia elongation correlates with localized biomechanical degradation in stress deprived tendon

Zonal variation in primary cilia elongation correlates with localized biomechanical degradation in stress deprived tendon

Cystin gene mutations cause autosomal recessive polycystic kidney disease associated with alteredMycexpression

The molecular structure of primary cilia revealed by cryo-electron tomography

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