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  1. Article ; Online: Base editing correction of OCRL in Lowe syndrome: ABE-mediated functional rescue in patient-derived fibroblasts.

    Chen, Siyu / Lo, Chien-Hui / Liu, Zhiquan / Wang, Qing / Ning, Ke / Li, Tingting / Sun, Yang

    Human molecular genetics

    2024  

    Abstract: Lowe syndrome, a rare X-linked multisystem disorder presenting with major abnormalities in the eyes, kidneys, and central nervous system, is caused by mutations in OCRL gene (NG_008638.1). Encoding an inositol polyphosphate 5-phosphatase, OCRL catalyzes ... ...

    Abstract Lowe syndrome, a rare X-linked multisystem disorder presenting with major abnormalities in the eyes, kidneys, and central nervous system, is caused by mutations in OCRL gene (NG_008638.1). Encoding an inositol polyphosphate 5-phosphatase, OCRL catalyzes the hydrolysis of PI(4,5)P2 into PI4P. There are no effective targeted treatments for Lowe syndrome. Here, we demonstrate a novel gene therapy for Lowe syndrome in patient fibroblasts using an adenine base editor (ABE) that can efficiently correct pathogenic point mutations. We show that ABE8e-NG-based correction of a disease-causing mutation in a Lowe patient-derived fibroblast line containing R844X mutation in OCRL gene, restores OCRL expression at mRNA and protein levels. It also restores cellular abnormalities that are hallmarks of OCRL dysfunction, including defects in ciliogenesis, microtubule anchoring, α-actinin distribution, and F-actin network. The study indicates that ABE-mediated gene therapy is a feasible treatment for Lowe syndrome, laying the foundation for therapeutic application of ABE in the currently incurable disease.
    Language English
    Publishing date 2024-04-01
    Publishing country England
    Document type Journal Article
    ZDB-ID 1108742-0
    ISSN 1460-2083 ; 0964-6906
    ISSN (online) 1460-2083
    ISSN 0964-6906
    DOI 10.1093/hmg/ddae045
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Compartmentalized ciliation changes of oligodendrocytes in aged mouse optic nerve.

    Ning, Ke / Tran, Matthew / Kowal, Tia J / Mesentier-Louro, Louise A / Sendayen, Brent E / Wang, Qing / Lo, Chien-Hui / Li, Tingting / Majumder, Rishab / Luo, Jian / Hu, Yang / Liao, Yaping Joyce / Sun, Yang

    Journal of neuroscience research

    2024  Volume 102, Issue 1, Page(s) e25273

    Abstract: Primary cilia are microtubule-based sensory organelles that project from the apical surface of most mammalian cells, including oligodendrocytes, which are myelinating cells of the central nervous system (CNS) that support critical axonal function. ... ...

    Abstract Primary cilia are microtubule-based sensory organelles that project from the apical surface of most mammalian cells, including oligodendrocytes, which are myelinating cells of the central nervous system (CNS) that support critical axonal function. Dysfunction of CNS glia is associated with aging-related white matter diseases and neurodegeneration, and ciliopathies are known to affect CNS white matter. To investigate age-related changes in ciliary profile, we examined ciliary length and frequency in the retinogeniculate pathway, a white matter tract commonly affected by diseases of aging but in which expression of cilia has not been characterized. We found expression of Arl13b, a marker of primary cilia, in a small group of Olig2-positive oligodendrocytes in the optic nerve, optic chiasm, and optic tract in young and aged C57BL/6 wild-type mice. While the ciliary length and ciliated oligodendrocyte cells were constant in young mice in the retinogeniculate pathway, there was a significant increase in ciliary length in the anterior optic nerve as compared to the aged animals. Morphometric analysis confirmed a specific increase in the ciliation rate of CC1
    MeSH term(s) Animals ; Mice ; Mice, Inbred C57BL ; Optic Nerve ; Oligodendroglia ; Neuroglia ; White Matter ; Mammals
    Language English
    Publishing date 2024-01-29
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 195324-2
    ISSN 1097-4547 ; 0360-4012
    ISSN (online) 1097-4547
    ISSN 0360-4012
    DOI 10.1002/jnr.25273
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Cilia-associated wound repair mediated by IFT88 in retinal pigment epithelium.

    Ning, Ke / Bhuckory, Mohajeet B / Lo, Chien-Hui / Sendayen, Brent E / Kowal, Tia J / Chen, Ming / Bansal, Ruchi / Chang, Kun-Che / Vollrath, Douglas / Berbari, Nicolas F / Mahajan, Vinit B / Hu, Yang / Sun, Yang

    Scientific reports

    2023  Volume 13, Issue 1, Page(s) 8205

    Abstract: Primary cilia are conserved organelles that integrate extracellular cues into intracellular signals and are critical for diverse processes, including cellular development and repair responses. Deficits in ciliary function cause multisystemic human ... ...

    Abstract Primary cilia are conserved organelles that integrate extracellular cues into intracellular signals and are critical for diverse processes, including cellular development and repair responses. Deficits in ciliary function cause multisystemic human diseases known as ciliopathies. In the eye, atrophy of the retinal pigment epithelium (RPE) is a common feature of many ciliopathies. However, the roles of RPE cilia in vivo remain poorly understood. In this study, we first found that mouse RPE cells only transiently form primary cilia. We then examined the RPE in the mouse model of Bardet-Biedl Syndrome 4 (BBS4), a ciliopathy associated with retinal degeneration in humans, and found that ciliation in BBS4 mutant RPE cells is disrupted early during development. Next, using a laser-induced injury model in vivo, we found that primary cilia in RPE reassemble in response to laser injury during RPE wound healing and then rapidly disassemble after the repair is completed. Finally, we demonstrated that RPE-specific depletion of primary cilia in a conditional mouse model of cilia loss promoted wound healing and enhanced cell proliferation. In summary, our data suggest that RPE cilia contribute to both retinal development and repair and provide insights into potential therapeutic targets for more common RPE degenerative diseases.
    MeSH term(s) Mice ; Humans ; Animals ; Retinal Pigment Epithelium ; Cilia/physiology ; Retinal Degeneration ; Ciliopathies ; Disease Models, Animal ; Tumor Suppressor Proteins ; Microtubule-Associated Proteins
    Chemical Substances IFT88 protein, human ; Tumor Suppressor Proteins ; BBS4 protein, mouse ; Microtubule-Associated Proteins
    Language English
    Publishing date 2023-05-21
    Publishing country England
    Document type Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-023-35099-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: INPP5E regulates CD3ζ enrichment at the immune synapse by phosphoinositide distribution control.

    Chiu, Tzu-Yuan / Lo, Chien-Hui / Lin, Yi-Hsuan / Lai, Yun-Di / Lin, Shan-Shan / Fang, Ya-Tian / Huang, Wei-Syun / Huang, Shen-Yan / Tsai, Pei-Yuan / Yang, Fu-Hua / Chong, Weng Man / Wu, Yi-Chieh / Tsai, Hsing-Chen / Liu, Ya-Wen / Hsu, Chia-Lin / Liao, Jung-Chi / Wang, Won-Jing

    Communications biology

    2023  Volume 6, Issue 1, Page(s) 911

    Abstract: The immune synapse, a highly organized structure formed at the interface between T lymphocytes and antigen-presenting cells (APCs), is essential for T cell activation and the adaptive immune response. It has been shown that this interface shares ... ...

    Abstract The immune synapse, a highly organized structure formed at the interface between T lymphocytes and antigen-presenting cells (APCs), is essential for T cell activation and the adaptive immune response. It has been shown that this interface shares similarities with the primary cilium, a sensory organelle in eukaryotic cells, although the roles of ciliary proteins on the immune synapse remain elusive. Here, we find that inositol polyphosphate-5-phosphatase E (INPP5E), a cilium-enriched protein responsible for regulating phosphoinositide localization, is enriched at the immune synapse in Jurkat T-cells during superantigen-mediated conjugation or antibody-mediated crosslinking of TCR complexes, and forms a complex with CD3ζ, ZAP-70, and Lck. Silencing INPP5E in Jurkat T-cells impairs the polarized distribution of CD3ζ at the immune synapse and correlates with a failure of PI(4,5)P
    MeSH term(s) Phosphoric Monoester Hydrolases ; Antibodies ; Phosphatidylinositols ; Receptors, Antigen, T-Cell
    Chemical Substances phosphoinositide 5-phosphatase (EC 3.1.3.36) ; Phosphoric Monoester Hydrolases (EC 3.1.3.2) ; Antibodies ; Phosphatidylinositols ; Receptors, Antigen, T-Cell
    Language English
    Publishing date 2023-09-05
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2399-3642
    ISSN (online) 2399-3642
    DOI 10.1038/s42003-023-05269-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Super-resolution microscopy reveals coupling between mammalian centriole subdistal appendages and distal appendages.

    Chong, Weng Man / Wang, Won-Jing / Lo, Chien-Hui / Chiu, Tzu-Yuan / Chang, Ting-Jui / Liu, You-Pi / Tanos, Barbara / Mazo, Gregory / Tsou, Meng-Fu Bryan / Jane, Wann-Neng / Yang, T Tony / Liao, Jung-Chi

    eLife

    2020  Volume 9

    Abstract: Subdistal appendages (sDAPs) are centriolar elements that are observed proximal to the distal appendages (DAPs) in vertebrates. Despite the obvious presence of sDAPs, structural and functional understanding of them remains elusive. Here, by combining ... ...

    Abstract Subdistal appendages (sDAPs) are centriolar elements that are observed proximal to the distal appendages (DAPs) in vertebrates. Despite the obvious presence of sDAPs, structural and functional understanding of them remains elusive. Here, by combining super-resolved localization analysis and CRISPR-Cas9 genetic perturbation, we find that although DAPs and sDAPs are primarily responsible for distinct functions in ciliogenesis and microtubule anchoring, respectively, the presence of one element actually affects the positioning of the other. Specifically, we find dual layers of both ODF2 and CEP89, where their localizations are differentially regulated by DAP and sDAP integrity. DAP depletion relaxes longitudinal occupancy of sDAP protein ninein to cover the DAP region, implying a role of DAPs in sDAP positioning. Removing sDAPs alter the distal border of centrosomal γ-tubulins, illustrating a new role of sDAPs. Together, our results provide an architectural framework for sDAPs that sheds light on functional understanding, surprisingly revealing coupling between DAPs and sDAPs.
    MeSH term(s) Cell Cycle ; Cell Cycle Proteins/chemistry ; Cells, Cultured ; Centrioles/ultrastructure ; Cytoskeletal Proteins/chemistry ; Heat-Shock Proteins/chemistry ; Humans ; Microscopy, Electron, Transmission/methods ; Microtubule-Associated Proteins/chemistry ; Nuclear Proteins/chemistry
    Chemical Substances CEP89 protein, human ; Cell Cycle Proteins ; Cep170 protein, human ; Cytoskeletal Proteins ; Heat-Shock Proteins ; Microtubule-Associated Proteins ; NIN protein, human ; Nuclear Proteins ; ODF2 protein, human
    Language English
    Publishing date 2020-04-03
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2687154-3
    ISSN 2050-084X ; 2050-084X
    ISSN (online) 2050-084X
    ISSN 2050-084X
    DOI 10.7554/eLife.53580
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Phosphorylation of CEP83 by TTBK2 is necessary for cilia initiation.

    Lo, Chien-Hui / Lin, I-Hsuan / Yang, T Tony / Huang, Yen-Chun / Tanos, Barbara E / Chou, Po-Chun / Chang, Chih-Wei / Tsay, Yeou-Guang / Liao, Jung-Chi / Wang, Won-Jing

    The Journal of cell biology

    2019  Volume 218, Issue 10, Page(s) 3489–3505

    Abstract: Primary cilia are microtubule-based organelles that play important roles in development and tissue homeostasis. Tau-tubulin kinase-2 (TTBK2) is genetically linked to spinocerebellar ataxia type 11, and its kinase activity is crucial for ciliogenesis. ... ...

    Abstract Primary cilia are microtubule-based organelles that play important roles in development and tissue homeostasis. Tau-tubulin kinase-2 (TTBK2) is genetically linked to spinocerebellar ataxia type 11, and its kinase activity is crucial for ciliogenesis. Although it has been shown that TTBK2 is recruited to the centriole by distal appendage protein CEP164, little is known about TTBK2 substrates associated with its role in ciliogenesis. Here, we perform superresolution microscopy and discover that serum starvation results in TTBK2 redistribution from the periphery toward the root of distal appendages. Our biochemical analyses uncover CEP83 as a bona fide TTBK2 substrate with four phosphorylation sites characterized. We also demonstrate that CEP164-dependent TTBK2 recruitment to distal appendages is required for subsequent CEP83 phosphorylation. Specifically, TTBK2-dependent CEP83 phosphorylation is important for early ciliogenesis steps, including ciliary vesicle docking and CP110 removal. In summary, our results reveal a molecular mechanism of kinase regulation in ciliogenesis and identify CEP83 as a key substrate of TTBK2 during cilia initiation.
    MeSH term(s) Cells, Cultured ; Cilia/metabolism ; HEK293 Cells ; Humans ; Microtubule-Associated Proteins/metabolism ; Phosphorylation ; Protein-Serine-Threonine Kinases/metabolism
    Chemical Substances CEP83 protein, human ; Microtubule-Associated Proteins ; tau-tubulin kinase (EC 2.7.1.11) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1)
    Language English
    Publishing date 2019-08-27
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 218154-x
    ISSN 1540-8140 ; 0021-9525
    ISSN (online) 1540-8140
    ISSN 0021-9525
    DOI 10.1083/jcb.201811142
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: DOCK6 promotes chemo- and radioresistance of gastric cancer by modulating WNT/β-catenin signaling and cancer stem cell traits.

    Chi, Hsiang-Cheng / Tsai, Chung-Ying / Wang, Chia-Siu / Yang, Huang-Yu / Lo, Chien-Hui / Wang, Won-Jing / Lee, Kam-Fai / Lai, Li-Yin / Hong, Ji-Hong / Chang, Yen-Fang / Tsai, Ming-Ming / Yeh, Chau-Ting / Wu, Cheng Heng / Hsieh, Ching-Chuan / Wang, Lu-Hai / Chen, Wei-Jan / Lin, Kwang-Huei

    Oncogene

    2020  Volume 39, Issue 37, Page(s) 5933–5949

    Abstract: Gastric cancer (GC) is the third leading cause of cancer-related mortality worldwide and prognosis after potentially curative gastrectomy remains poor. Administration of GC-targeting molecules in combination with adjuvant chemo- or radiotherapy following ...

    Abstract Gastric cancer (GC) is the third leading cause of cancer-related mortality worldwide and prognosis after potentially curative gastrectomy remains poor. Administration of GC-targeting molecules in combination with adjuvant chemo- or radiotherapy following surgical resection has been proposed as a potentially effective treatment option. Here, we have identified DOCK6, a guanine nucleotide exchange factor (GEF) for Rac1 and CDC42, as an independent biomarker for GC prognosis. Clinical findings indicate the positive correlation of higher DOCK6 expression with tumor size, depth of invasion, lymph node metastasis, vascular invasion, and pathological stage. Furthermore, elevated DOCK6 expression was significantly associated with shorter cumulative survival in both univariate and multivariate analyses. Gene ontology analysis of three independent clinical GC cohorts revealed significant involvement of DOCK6-correlated genes in the WNT/β-catenin signaling pathway. Ectopic expression of DOCK6 promoted GC cancer stem cell (CSC) characteristics and chemo- or radioresistance concomitantly through Rac1 activation. Conversely, depletion of DOCK6 suppressed CSC phenotypes and progression of GC, further demonstrating the pivotal role of DOCK6 in GC progression. Our results demonstrate a novel mechanistic link between DOCK6, Rac1, and β-catenin in GCCSC for the first time, supporting the utility of DOCK6 as an independent marker of GC.
    MeSH term(s) Animals ; Cell Line, Tumor ; Cell Movement/genetics ; Cell Proliferation/genetics ; Disease Models, Animal ; Disease Progression ; Drug Resistance, Neoplasm/genetics ; Gene Expression Regulation, Neoplastic ; Gene Silencing ; Guanine Nucleotide Exchange Factors/genetics ; Guanine Nucleotide Exchange Factors/metabolism ; Heterografts ; Humans ; Immunohistochemistry ; Immunophenotyping ; Mice ; Neoplastic Stem Cells/metabolism ; Phenotype ; Radiation Tolerance/genetics ; Stomach Neoplasms/genetics ; Stomach Neoplasms/metabolism ; Stomach Neoplasms/pathology ; Stomach Neoplasms/therapy ; Wnt Signaling Pathway
    Chemical Substances DOCK6 protein, human ; Guanine Nucleotide Exchange Factors
    Language English
    Publishing date 2020-08-04
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 639046-8
    ISSN 1476-5594 ; 0950-9232
    ISSN (online) 1476-5594
    ISSN 0950-9232
    DOI 10.1038/s41388-020-01390-0
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