Essential role of nephrocystin in photoreceptor intraflagellar transport in mouse

Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan, Republic of China.
Human Molecular Genetics (Impact Factor: 6.39). 03/2009; 18(9):1566-77. DOI: 10.1093/hmg/ddp068
Source: PubMed


Nephrocystin mutations account for the vast majority of juvenile nephronophthisis, the most common inherited cause of renal
failure in children. Nephrocystin has been localized to the ciliary transition zone of epithelial cells or its analogous structure,
connecting cilium of retinal photoreceptors. Thus, the retinal degeneration associated with nephronophthisis may be explained
by a functional ciliary defect. However, the function of nephrocystin in cilium assembly and maintenance of common epithelial
cells and photoreceptors is still obscure. Here, we used Nphp1-targeted mutant mice and transgenic mice expressing EmGFP-tagged nephrocystin to demonstrate that nephrocystin located at
connecting cilium axoneme can affect the sorting mechanism and transportation efficiency of the traffic machinery between
inner and outer segments of photoreceptors. This traffic machinery is now recognized as intraflagellar transport (IFT); a
microtubule-based transport system consisting of motors, IFT particles and associated cargo molecules. Nephrocystin seems
to control some of the IFT particle components moving along the connecting cilia so as to regulate this inter-segmental traffic.
Our novel findings provide a clue to unraveling the regulatory mechanism of nephrocystin in IFT machinery.

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Available from: Ellian Wang, Jan 06, 2016
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    • "It allowed the authors not only to identify three interconnected functional modules, but to also identify three new ciliopathy genes: Sang et al. 2011 identified ATXN10 and TCTN2, and Garcia-Gonzalo et al. 2011 identified TCTN1. The first module, the “nephronophthisis NPHP module” identified in Sang et al. 2011, was composed of NPHP1/nephrocystin-1, which was previously suggested to take part in the regulation of cargo and IFT ciliary entry [61]. NPHP4 and RPGRIP1L (also components of the NPHP module) were also localized to the transition zone and cell-cell boundaries. "
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    ABSTRACT: Recent studies of the primary cilium have begun to provide further insights into ciliary ultrastructure, with an emerging picture of complex compartmentalization and molecular components that combine in functional modules. Many proteins that are mutated in ciliopathies are localized to the transition zone, a compartment of the proximal region of the cilium. The loss of these components can disrupt ciliary functions such as the control of protein entry and exit from the cilium, the possible trafficking of essential ciliary components, and the regulation of signaling cascades and control of the cell cycle. The discovery of functional modules within the primary cilium may help in understanding the variable phenotypes and pleiotropy in ciliopathies.
    Full-text · Article · Jul 2012 · Cilia
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    • "Instead, Plk1 co-localized with nephrocystin-1 at the transition zone, the region connecting the basal body, the ciliary axoneme and the plasma membrane. The transition zone has been implicated to function as ciliary gatekeeper controlling trafficking of ciliary proteins [41], [42] and many transition zone proteins including the nephrocystins have been suggested to be involved in this function [11], [43], [44]. In our study, Plk1 induced the phosphorylation of the transition zone protein nephrocystin-1. "
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    ABSTRACT: Polo-like kinase (Plk1) plays a central role in regulating the cell cycle. Plk1-mediated phosphorylation is essential for centrosome maturation, and for numerous mitotic events. Although Plk1 localizes to multiple subcellular sites, a major site of action is the centrosomes, which supports mitotic functions in control of bipolar spindle formation. In G0 or G1 untransformed cells, the centriolar core of the centrosome differentiates into the basal body of the primary cilium. Primary cilia are antenna-like sensory organelles dynamically regulated during the cell cycle. Whether Plk1 has a role in ciliary biology has never been studied. Nephrocystin-1 (NPHP1) is a ciliary protein; loss of NPHP1 in humans causes nephronophthisis (NPH), an autosomal-recessive cystic kidney disease. We here demonstrate that Plk1 colocalizes with nephrocystin-1 to the transition zone of primary cilia in epithelial cells. Plk1 co-immunoprecipitates with NPHP1, suggesting it is part of the nephrocystin protein complex. We identified a candidate Plk1 phosphorylation motif (D/E-X-S/T-φ-X-D/E) in nephrocystin-1, and demonstrated in vitro that Plk1 phosphorylates the nephrocystin N-terminus, which includes the specific PLK1 phosphorylation motif. Further, induced disassembly of primary cilia rapidly evoked Plk1 kinase activity, while small molecule inhibition of Plk1 activity or RNAi-mediated downregulation of Plk1 limited the first and second phase of ciliary disassembly. These data identify Plk1 as a novel transition zone signaling protein, suggest a function of Plk1 in cilia dynamics, and link Plk1 to the pathogenesis of NPH and potentially other cystic kidney diseases.
    Full-text · Article · Jun 2012 · PLoS ONE
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    • "Patients with Joubert syndrome may also develop nephronophthisis and/or retinal dystrophy. Knockout mice for Nphp1 exhibit general disorganization of the inner and outer segments of the retina along with remarkable retinal degeneration (Jiang et al. 2009). The function of MALL is less understood, with current data suggesting that it is a proteolipid involved in cholesterol homeostasis (de Marco et al. 2001). "
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    ABSTRACT: Age-related macular degeneration (AMD) is a complex genetic disease, with many loci demonstrating appreciable attributable disease risk. Despite significant progress toward understanding the genetic and environmental etiology of AMD, identification of additional risk factors is necessary to fully appreciate and treat AMD pathology. In this study, we investigated copy number variants (CNVs) as potential AMD risk variants in a cohort of 400 AMD patients and 500 AMD-free controls ascertained at the University of Iowa. We used three publicly available copy number programs to analyze signal intensity data from Affymetrix GeneChip SNP Microarrays. CNVs were ranked based on prevalence in the disease cohort and absence from the control group; high interest CNVs were subsequently confirmed by qPCR. While we did not observe a single-locus "risk CNV" that could account for a major fraction of AMD, we identified several rare and overlapping CNVs containing or flanking compelling candidate genes such as NPHP1 and EFEMP1. These and other candidate genes highlighted by this study deserve further scrutiny as sources of genetic risk for AMD.
    Full-text · Article · Oct 2010 · Human Genetics
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