OFD1 and Flotillins Are Integral Components of a Ciliary Signaling Protein Complex Organized by Polycystins in Renal Epithelia and Odontoblasts

Jerman, Stephanie; Ward, Heather H.; Lee, Rebecca; Lopes, Carla A.M.; Fry, Andrew M.; MacDougall, Mary; Wandinger‐Ness, Angela

doi:10.1371/journal.pone.0106330

Cited by 15 publications

(11 citation statements)

References 62 publications

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“…As a known cilia protein [ 49 ] but no report in retina tissue, our results showed that Ofd1 was localized to the photoreceptor outer segments as shown by immunostaining in rat retina. Retina connecting cilium connects the inner and outer segments of the photoreceptor, mediating bi-directional transport of phototransducing proteins required for vision.…”

Section: Discussionsupporting

confidence: 46%

OFD1, as a Ciliary Protein, Exhibits Neuroprotective Function in Photoreceptor Degeneration Models

Wang¹,

Chen²,

Wang³

et al. 2016

PLoS ONE

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Ofd1 is a newly identified causative gene for Retinitis pigmentosa (RP), a photoreceptor degenerative disease. This study aimed to examine Ofd1 localization in retina and further to investigate its function in photoreceptor degeneration models. Ofd1 localization in rat retina was examined using immunofluorescence. N-methyl-N-nitrosourea (MNU)-induced rats and Royal College of Surgeons (RCS) rats were used as photoreceptor degeneration models. The expression pattern of Ofd1, other ciliary associated genes and Wnt signaling pathway genes were examined in rat models. Furthermore, pEGFP-Ofd1-CDS and pSUPER-Ofd1-shRNA were constructed to overexpress and knockdown the expression level in 661W and R28 cells. MNU was also used to induce cell death. Cilia formation was observed using immunocytochemistry (ICC). Reactive oxygen species (ROS) were detected using the 2', 7'-Dichlorofluorescin diacetate (DCFH-DA) assay. Apoptosis genes expression was examined using qRT-PCR, Western blotting and fluorescence-activated cell sorting (FACS). Ofd1 localized to outer segments of rat retina photoreceptors. Ofd1 and other ciliary proteins expression levels increased from the 1st and 4th postnatal weeks and decreased until the 6th week in the RCS rats, while their expression consistently decreased from the 1st and 7th day in the MNU rats. Moreover, Wnt signaling pathway proteins expression was significantly up-regulated in both rat models. Knockdown of Ofd1 expression resulted in a smaller population, shorter length of cell cilia, and lower cell viability. Ofd1 overexpression partially attenuated MNU toxic effects by reducing ROS levels and mitigating apoptosis. To the best of our knowledge, this is the first study demonstrating Ofd1 localization and its function in rat retina and in retinal degeneration rat models. Ofd1 plays a role in controlling photoreceptor cilium length and number. Importantly, it demonstrates a neuroprotective function by protecting the photoreceptor from oxidative stress and apoptosis. These data have expanded our understanding of Ofd1 function beyond cilia, and we concluded that ofd1 neuroprotection could be a potential treatment strategy in retina degeneration models.

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Section: Discussionsupporting

confidence: 46%

OFD1, as a Ciliary Protein, Exhibits Neuroprotective Function in Photoreceptor Degeneration Models

Wang¹,

Chen²,

Wang³

et al. 2016

PLoS ONE

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“…The function of PKD2 is suppressed by PtdIns(4,5)P 2 . [98] The interaction between EGFR and PKD2 may be involved in the mechanosensation that is necessary for directed migration of these cells. [85,93] Therefore, EGF signaling can sensitize the primary cilium-based mechanosensation by reducing the threshold of PKD2 for activation by mechanical stimulation.…”

Section: Egf Signaling Regulates Mechanosensation Through Primary Ciliamentioning

confidence: 99%

Primary Cilia as Signaling Hubs in Health and Disease

et al. 2018

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Primary cilia detect extracellular cues and transduce these signals into cells to regulate proliferation, migration, and differentiation. Here, the function of primary cilia as signaling hubs of growth factors and morphogens is in focus. First, the molecular mechanisms regulating the assembly and disassembly of primary cilia are described. Then, the role of primary cilia in mediating growth factor and morphogen signaling to maintain human health and the potential mechanisms by which defects in these pathways contribute to human diseases, such as ciliopathy, obesity, and cancer are described. Furthermore, a novel signaling pathway by which certain growth factors stimulate cell proliferation through suppression of ciliogenesis is also described, suggesting novel therapeutic targets in cancer.

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“…New mechanisms whereby non-cilia associated proteins impact cilia structure and function have been identified [29, 33]. The interactions of diverse cilia-associated cystic kidney disease proteins continue to be investigated, with an expanding list of proteins that comprise the polycystin cilia signaling complex [36, 37]. A new technique to directly measure cilia calcium concentrations and channel activity demonstrated that cilia have a separate calcium signaling microenvironment modulated by a unique calcium channel [30, 31].…”

Section: Resultsmentioning

confidence: 99%

“…Jerman et al [37] found that OFD1 is part of the large signaling complex that contains PC1, PC2, EGFR, and flotillins. In human ADPKD cells, they further showed that loss of PC1 cilia localization was associated with loss of cilia localization of the other protein complex members.…”

Section: Recent Insights and Controversiesmentioning

confidence: 99%

The role of cilia in the pathogenesis of cystic kidney disease

Dell

2015

Current Opinion in Pediatrics

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Purpose of review Primary (immotile) cilia are specialized organelles present on most cell types. Almost all of proteins associated with a broad spectrum of human cystic kidney diseases have been localized to the region in or around the cilia. Abnormal cilia structure and/or function have been reported in animal models and human cystic kidneys. The goal of this review is to discuss current understanding of the mechanisms by which abnormal genes/proteins and cilia interact to potentially influence renal cystogenesis. Recent findings Novel direct recording of cilia calcium levels/channel activity suggest that cilia form a calcium-mediated signaling microenvironment separate from the cytoplasm, which could provide a mechanism for cilia-specific downstream signaling. Genetic-based studies confirm that cilia are not required for cystogenesis but modulate cystic kidney disease severity through a novel, undefined mechanism. Mechanisms by which both cilia-associated and non-cilia associated proteins can alter cilia structure/function have also been identified. Summary Considerable progress has been made in defining the mechanisms by which abnormal genes and proteins affect cilia structure and function. However, the exact mechanisms by which these interactions cause renal cyst formation and progression of cystic kidney disease are still unknown.

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OFD1 and Flotillins Are Integral Components of a Ciliary Signaling Protein Complex Organized by Polycystins in Renal Epithelia and Odontoblasts

Cited by 15 publications

References 62 publications

OFD1, as a Ciliary Protein, Exhibits Neuroprotective Function in Photoreceptor Degeneration Models

OFD1, as a Ciliary Protein, Exhibits Neuroprotective Function in Photoreceptor Degeneration Models

Primary Cilia as Signaling Hubs in Health and Disease

The role of cilia in the pathogenesis of cystic kidney disease

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