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  1. Article: Identification of new ciliary signaling pathways in the brain and insights into neurological disorders.

    Loukil, Abdelhalim / Ebright, Emma / Uezu, Akiyoshi / Gao, Yudong / Soderling, Scott H / Goetz, Sarah C

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Primary cilia are conserved sensory hubs essential for signaling transduction and embryonic development. Ciliary dysfunction causes a variety of developmental syndromes with neurological features and cognitive impairment, whose basis mostly remains ... ...

    Abstract Primary cilia are conserved sensory hubs essential for signaling transduction and embryonic development. Ciliary dysfunction causes a variety of developmental syndromes with neurological features and cognitive impairment, whose basis mostly remains unknown. Despite connections to neural function, the primary cilium remains an overlooked organelle in the brain. Most neurons have a primary cilium; however, it is still unclear how this organelle modulates brain architecture and function, given the lack of any systemic dissection of neuronal ciliary signaling. Here, we present the first in vivo glance at the molecular composition of cilia in the mouse brain. We have adapted
    Language English
    Publishing date 2023-12-21
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.12.20.572700
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: A complex of distal appendage-associated kinases linked to human disease regulates ciliary trafficking and stability.

    Loukil, Abdelhalim / Barrington, Chloe / Goetz, Sarah C

    Proceedings of the National Academy of Sciences of the United States of America

    2021  Volume 118, Issue 16

    Abstract: Cilia biogenesis is a complex, multistep process involving the coordination of multiple cellular trafficking pathways. Despite the importance of ciliogenesis in mediating the cellular response to cues from the microenvironment, we have only a limited ... ...

    Abstract Cilia biogenesis is a complex, multistep process involving the coordination of multiple cellular trafficking pathways. Despite the importance of ciliogenesis in mediating the cellular response to cues from the microenvironment, we have only a limited understanding of the regulation of cilium assembly. We previously identified Tau tubulin kinase 2 (TTBK2) as a key regulator of ciliogenesis. Here, using CRISPR kinome and biotin identification screening, we identify the CK2 catalytic subunit CSNK2A1 as an important modulator of TTBK2 function in cilia trafficking. Superresolution microscopy reveals that CSNK2A1 is a centrosomal protein concentrated at the mother centriole and associated with the distal appendages.
    MeSH term(s) Animals ; Casein Kinase II/metabolism ; Casein Kinase II/physiology ; Cell Line ; Centrioles/metabolism ; Cilia/metabolism ; Cilia/physiology ; Ciliopathies/physiopathology ; HEK293 Cells ; Hedgehog Proteins/metabolism ; Humans ; Mice ; Neurodevelopmental Disorders/genetics ; Neurodevelopmental Disorders/physiopathology ; Protein Serine-Threonine Kinases/metabolism ; Protein Serine-Threonine Kinases/physiology
    Chemical Substances Hedgehog Proteins ; tau-tubulin kinase (EC 2.7.1.11) ; CSNK2A1 protein, human (EC 2.7.11.1) ; Casein Kinase II (EC 2.7.11.1) ; Protein Serine-Threonine Kinases (EC 2.7.11.1)
    Language English
    Publishing date 2021-04-14
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2018740118
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: The daughter centriole controls ciliogenesis by regulating Neurl-4 localization at the centrosome.

    Loukil, Abdelhalim / Tormanen, Kati / Sütterlin, Christine

    The Journal of cell biology

    2017  Volume 216, Issue 5, Page(s) 1287–1300

    Abstract: The two centrioles of the centrosome differ in age and function. Although the mother centriole mediates most centrosome-dependent processes, the role of the daughter remains poorly understood. A recent study has implicated the daughter centriole in ... ...

    Abstract The two centrioles of the centrosome differ in age and function. Although the mother centriole mediates most centrosome-dependent processes, the role of the daughter remains poorly understood. A recent study has implicated the daughter centriole in centriole amplification in multiciliated cells, but its contribution to primary ciliogenesis is unclear. We found that manipulations that prevent daughter centriole formation or induce its separation from the mother abolish ciliogenesis. This defect was caused by stabilization of the negative ciliogenesis regulator CP110 and was corrected by CP110 depletion. CP110 dysregulation may be caused by effects on Neurl-4, a daughter centriole-associated ubiquitin ligase cofactor, which was required for ciliogenesis. Centrosome-targeted Neurl-4 was sufficient to restore ciliogenesis in cells with manipulated daughter centrioles. Interestingly, early during ciliogenesis, Neurl-4 transiently associated with the mother centriole in a process that required mother-daughter centriole proximity. Our data support a model in which the daughter centriole promotes ciliogenesis through Neurl-4-dependent regulation of CP110 levels at the mother centriole.
    MeSH term(s) Carrier Proteins/metabolism ; Cell Cycle Proteins/metabolism ; Cells, Cultured ; Centrioles/metabolism ; Centrosome/metabolism ; Humans ; Microtubule-Associated Proteins/metabolism ; Phosphoproteins/metabolism
    Chemical Substances CCP110 protein, human ; Carrier Proteins ; Cell Cycle Proteins ; Microtubule-Associated Proteins ; Neurl4 protein, human ; Phosphoproteins
    Language English
    Publishing date 2017-05-01
    Publishing country United States
    Document type Journal Article
    ZDB-ID 218154-x
    ISSN 1540-8140 ; 0021-9525
    ISSN (online) 1540-8140
    ISSN 0021-9525
    DOI 10.1083/jcb.201608119
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Multiple ciliary localization signals control INPP5E ciliary targeting.

    Cilleros-Rodriguez, Dario / Martin-Morales, Raquel / Barbeito, Pablo / Deb Roy, Abhijit / Loukil, Abdelhalim / Sierra-Rodero, Belen / Herranz, Gonzalo / Pampliega, Olatz / Redrejo-Rodriguez, Modesto / Goetz, Sarah C / Izquierdo, Manuel / Inoue, Takanari / Garcia-Gonzalo, Francesc R

    eLife

    2022  Volume 11

    Abstract: Primary cilia are sensory membrane protrusions whose dysfunction causes ciliopathies. INPP5E is a ciliary phosphoinositide phosphatase mutated in ciliopathies like Joubert syndrome. INPP5E regulates numerous ciliary functions, but how it accumulates in ... ...

    Abstract Primary cilia are sensory membrane protrusions whose dysfunction causes ciliopathies. INPP5E is a ciliary phosphoinositide phosphatase mutated in ciliopathies like Joubert syndrome. INPP5E regulates numerous ciliary functions, but how it accumulates in cilia remains poorly understood. Herein, we show INPP5E ciliary targeting requires its folded catalytic domain and is controlled by four conserved ciliary localization signals (CLSs): LLxPIR motif (CLS1), W383 (CLS2), FDRxLYL motif (CLS3) and CaaX box (CLS4). We answer two long-standing questions in the field. First, partial CLS1-CLS4 redundancy explains why CLS4 is dispensable for ciliary targeting. Second, the essential need for CLS2 clarifies why CLS3-CLS4 are together insufficient for ciliary accumulation. Furthermore, we reveal that some Joubert syndrome mutations perturb INPP5E ciliary targeting, and clarify how each CLS works: (i) CLS4 recruits PDE6D, RPGR and ARL13B, (ii) CLS2-CLS3 regulate association to TULP3, ARL13B, and CEP164, and (iii) CLS1 and CLS4 cooperate in ATG16L1 binding. Altogether, we shed light on the mechanisms of INPP5E ciliary targeting, revealing a complexity without known parallels among ciliary cargoes.
    MeSH term(s) Abnormalities, Multiple ; Cerebellum/abnormalities ; Cilia/metabolism ; Ciliopathies ; Eye Abnormalities ; Eye Proteins/metabolism ; Humans ; Kidney Diseases, Cystic/genetics ; Kidney Diseases, Cystic/metabolism ; Phosphoric Monoester Hydrolases/genetics ; Phosphoric Monoester Hydrolases/metabolism ; Retina/abnormalities
    Chemical Substances Eye Proteins ; RPGR protein, human ; Phosphoric Monoester Hydrolases (EC 3.1.3.2) ; phosphoinositide 5-phosphatase (EC 3.1.3.36)
    Language English
    Publishing date 2022-09-05
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 2687154-3
    ISSN 2050-084X ; 2050-084X
    ISSN (online) 2050-084X
    ISSN 2050-084X
    DOI 10.7554/eLife.78383
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: Cyclin A2: At the crossroads of cell cycle and cell invasion.

    Loukil, Abdelhalim / Cheung, Caroline T / Bendris, Nawal / Lemmers, Bénédicte / Peter, Marion / Blanchard, Jean Marie

    World journal of biological chemistry

    2015  Volume 6, Issue 4, Page(s) 346–350

    Abstract: Cyclin A2 is an essential regulator of the cell division cycle through the activation of kinases that participate to the regulation of S phase as well as the mitotic entry. However, whereas its degradation by the proteasome in mid mitosis was thought to ... ...

    Abstract Cyclin A2 is an essential regulator of the cell division cycle through the activation of kinases that participate to the regulation of S phase as well as the mitotic entry. However, whereas its degradation by the proteasome in mid mitosis was thought to be essential for mitosis to proceed, recent observations show that a small fraction of cyclin A2 persists beyond metaphase and is degraded by autophagy. Its implication in the control of cytoskeletal dynamics and cell movement has unveiled its role in the modulation of RhoA activity. Since this GTPase is involved in both cell rounding early in mitosis and later, in the formation of the cleavage furrow, this suggests that cyclin A2 is a novel actor in cytokinesis. Taken together, these data point to this cyclin as a potential mediator of cell-niche interactions whose dysregulation could be taken as a hallmark of metastasis.
    Language English
    Publishing date 2015-12-01
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 2564793-3
    ISSN 1949-8454
    ISSN 1949-8454
    DOI 10.4331/wjbc.v6.i4.346
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Foci of cyclin A2 interact with actin and RhoA in mitosis.

    Loukil, Abdelhalim / Izard, Fanny / Georgieva, Mariya / Mashayekhan, Shaereh / Blanchard, Jean-Marie / Parmeggiani, Andrea / Peter, Marion

    Scientific reports

    2016  Volume 6, Page(s) 27215

    Abstract: Cyclin A2 is a key player in the regulation of the cell cycle. Its degradation in mid-mitosis depends primarily on the ubiquitin-proteasome system (UPS), while autophagy also contributes. However, a fraction of cyclin A2 persists beyond metaphase. In ... ...

    Abstract Cyclin A2 is a key player in the regulation of the cell cycle. Its degradation in mid-mitosis depends primarily on the ubiquitin-proteasome system (UPS), while autophagy also contributes. However, a fraction of cyclin A2 persists beyond metaphase. In this work, we focus on cyclin A2-rich foci detected in mitosis by high resolution imaging and analyse their movements. We demonstrate that cyclin A2 interacts with actin and RhoA during mitosis, and that cyclin A2 depletion induces a dramatic decrease in active RhoA in mitosis. Our data suggest cyclin A2 participation in RhoA activation in late mitosis.
    Language English
    Publishing date 2016-06-09
    Publishing country England
    Document type Journal Article
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/srep27215
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: High-resolution live-cell imaging reveals novel cyclin A2 degradation foci involving autophagy.

    Loukil, Abdelhalim / Zonca, Manuela / Rebouissou, Cosette / Baldin, Véronique / Coux, Olivier / Biard-Piechaczyk, Martine / Blanchard, Jean-Marie / Peter, Marion

    Journal of cell science

    2014  Volume 127, Issue Pt 10, Page(s) 2145–2150

    Abstract: Cyclin A2 is a key player in the regulation of the cell cycle. Its degradation in mid-mitosis relies on the ubiquitin-proteasome system (UPS). Using high-resolution microscopic imaging, we find that cyclin A2 persists beyond metaphase. Indeed, we ... ...

    Abstract Cyclin A2 is a key player in the regulation of the cell cycle. Its degradation in mid-mitosis relies on the ubiquitin-proteasome system (UPS). Using high-resolution microscopic imaging, we find that cyclin A2 persists beyond metaphase. Indeed, we identify a novel cyclin-A2-containing compartment that forms dynamic foci. Förster (or fluorescence) resonance energy transfer (FRET) and fluorescence lifetime imaging microscopy (FLIM) analyses show that cyclin A2 ubiquitylation takes place predominantly in these foci before spreading throughout the cell. Moreover, inhibition of autophagy in proliferating cells induces the stabilisation of a subset of cyclin A2, whereas induction of autophagy accelerates the degradation of cyclin A2, thus showing that autophagy is a novel regulator of cyclin A2 degradation.
    MeSH term(s) Autophagy/physiology ; Cell Communication ; Cyclin A2/metabolism ; Fluorescence Resonance Energy Transfer/methods ; Humans ; MCF-7 Cells ; Microscopy, Fluorescence/methods ; Proteasome Endopeptidase Complex/metabolism ; Ubiquitin/metabolism
    Chemical Substances CCNA2 protein, human ; Cyclin A2 ; Ubiquitin ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
    Language English
    Publishing date 2014-05-15
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2993-2
    ISSN 1477-9137 ; 0021-9533
    ISSN (online) 1477-9137
    ISSN 0021-9533
    DOI 10.1242/jcs.139188
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Cyclin A2

    Bendris Nawal / Loukil Abdelhalim / Cheung Caroline / Arsic Nikola / Rebouissou Cosette / Hipskind Robert / Peter Marion / Lemmers Bénédicte / Blanchard Jean Marie

    Biomolecular Concepts, Vol 3, Iss 6, Pp 535-

    a genuine cell cycle regulator?

    2012  Volume 543

    Abstract: Cyclin A2 belongs to the core cell cycle regulators and participates in the control of both S phase and mitosis. However, several observations suggest that it is also endowed with other functions, and our recent data shed light on its involvement in ... ...

    Abstract Cyclin A2 belongs to the core cell cycle regulators and participates in the control of both S phase and mitosis. However, several observations suggest that it is also endowed with other functions, and our recent data shed light on its involvement in cytoskeleton dynamic and cell motility. From the transcription of its gene to its posttranslational modifications, cyclin A2 regulation reveals the complexity of the regulatory network shaping cell cycle progression. We summarize our current knowledge on this cell cycle regulator and discuss recent findings raising the possibility that cyclin A2 might play a much broader role in epithelial tissues homeostasis.
    Keywords cytoskeleton ; degradation ; invasion ; mitosis ; rho gtpases ; s phase ; transcription ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2012-12-01T00:00:00Z
    Publisher De Gruyter
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article: Cyclin A2: a genuine cell cycle regulator?

    Bendris, Nawal / Loukil, Abdelhalim / Cheung, Caroline / Arsic, Nikola / Rebouissou, Cosette / Hipskind, Robert / Peter, Marion / Lemmers, Bénédicte / Blanchard, Jean Marie

    Biomolecular concepts

    2012  Volume 3, Issue 6, Page(s) 535–543

    Abstract: Abstract Cyclin A2 belongs to the core cell cycle regulators and participates in the control of both S phase and mitosis. However, several observations suggest that it is also endowed with other functions, and our recent data shed light on its ... ...

    Abstract Abstract Cyclin A2 belongs to the core cell cycle regulators and participates in the control of both S phase and mitosis. However, several observations suggest that it is also endowed with other functions, and our recent data shed light on its involvement in cytoskeleton dynamic and cell motility. From the transcription of its gene to its posttranslational modifications, cyclin A2 regulation reveals the complexity of the regulatory network shaping cell cycle progression. We summarize our current knowledge on this cell cycle regulator and discuss recent findings raising the possibility that cyclin A2 might play a much broader role in epithelial tissues homeostasis.
    Language English
    Publishing date 2012-12
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 2557908-3
    ISSN 1868-503X ; 1868-5021
    ISSN (online) 1868-503X
    ISSN 1868-5021
    DOI 10.1515/bmc-2012-0027
    Database MEDical Literature Analysis and Retrieval System OnLINE

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