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  1. Article ; Online: CCP1, a Tubulin Deglutamylase, Increases Survival of Rodent Spinal Cord Neurons following Glutamate-Induced Excitotoxicity.

    Ramadan, Yasmin H / Gu, Amanda / Ross, Nicole / McEwan, Sara A / Barr, Maureen M / Firestein, Bonnie L / O'Hagan, Robert

    eNeuro

    2021  Volume 8, Issue 2

    Abstract: Microtubules (MTs) are cytoskeletal elements that provide structural support and act as roadways for intracellular transport in cells. MTs are also needed for neurons to extend and maintain long axons and dendrites that establish connectivity to transmit ...

    Abstract Microtubules (MTs) are cytoskeletal elements that provide structural support and act as roadways for intracellular transport in cells. MTs are also needed for neurons to extend and maintain long axons and dendrites that establish connectivity to transmit information through the nervous system. Therefore, in neurons, the ability to independently regulate cytoskeletal stability and MT-based transport in different cellular compartments is essential. Posttranslational modification of MTs is one mechanism by which neurons regulate the cytoskeleton. The carboxypeptidase CCP1 negatively regulates posttranslational polyglutamylation of MTs. In mammals, loss of CCP1, and the resulting hyperglutamylation of MTs, causes neurodegeneration. It has also long been known that CCP1 expression is activated by neuronal injury; however, whether CCP1 plays a neuroprotective role after injury is unknown. Using shRNA-mediated knock-down of CCP1 in embryonic rat spinal cord cultures, we demonstrate that CCP1 protects spinal cord neurons from excitotoxic death. Unexpectedly, excitotoxic injury reduced CCP1 expression in our system. We previously demonstrated that the CCP1 homolog in
    MeSH term(s) Animals ; Carboxypeptidases ; Gene Knockdown Techniques ; Glutamic Acid ; Neurons ; Rats ; Rodentia ; Spinal Cord ; Spinal Cord Injuries ; Tubulin
    Chemical Substances Tubulin ; Glutamic Acid (3KX376GY7L) ; Carboxypeptidases (EC 3.4.-)
    Language English
    Publishing date 2021-04-01
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2800598-3
    ISSN 2373-2822 ; 2373-2822
    ISSN (online) 2373-2822
    ISSN 2373-2822
    DOI 10.1523/ENEURO.0431-20.2021
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Mutation of NEKL-4/NEK10 and TTLL genes suppress neuronal ciliary degeneration caused by loss of CCPP-1 deglutamylase function.

    Power, Kade M / Akella, Jyothi S / Gu, Amanda / Walsh, Jonathon D / Bellotti, Sebastian / Morash, Margaret / Zhang, Winnie / Ramadan, Yasmin H / Ross, Nicole / Golden, Andy / Smith, Harold E / Barr, Maureen M / O'Hagan, Robert

    PLoS genetics

    2020  Volume 16, Issue 10, Page(s) e1009052

    Abstract: Ciliary microtubules are subject to post-translational modifications that act as a "Tubulin Code" to regulate motor traffic, binding proteins and stability. In humans, loss of CCP1, a cytosolic carboxypeptidase and tubulin deglutamylating enzyme, causes ... ...

    Abstract Ciliary microtubules are subject to post-translational modifications that act as a "Tubulin Code" to regulate motor traffic, binding proteins and stability. In humans, loss of CCP1, a cytosolic carboxypeptidase and tubulin deglutamylating enzyme, causes infantile-onset neurodegeneration. In C. elegans, mutations in ccpp-1, the homolog of CCP1, result in progressive degeneration of neuronal cilia and loss of neuronal function. To identify genes that regulate microtubule glutamylation and ciliary integrity, we performed a forward genetic screen for suppressors of ciliary degeneration in ccpp-1 mutants. We isolated the ttll-5(my38) suppressor, a mutation in a tubulin tyrosine ligase-like glutamylase gene. We show that mutation in the ttll-4, ttll-5, or ttll-11 gene suppressed the hyperglutamylation-induced loss of ciliary dye filling and kinesin-2 mislocalization in ccpp-1 cilia. We also identified the nekl-4(my31) suppressor, an allele affecting the NIMA (Never in Mitosis A)-related kinase NEKL-4/NEK10. In humans, NEK10 mutation causes bronchiectasis, an airway and mucociliary transport disorder caused by defective motile cilia. C. elegans NEKL-4 localizes to the ciliary base but does not localize to cilia, suggesting an indirect role in ciliary processes. This work defines a pathway in which glutamylation, a component of the Tubulin Code, is written by TTLL-4, TTLL-5, and TTLL-11; is erased by CCPP-1; is read by ciliary kinesins; and its downstream effects are modulated by NEKL-4 activity. Identification of regulators of microtubule glutamylation in diverse cellular contexts is important to the development of effective therapies for disorders characterized by changes in microtubule glutamylation. By identifying C. elegans genes important for neuronal and ciliary stability, our work may inform research into the roles of the tubulin code in human ciliopathies and neurodegenerative diseases.
    MeSH term(s) Animals ; Caenorhabditis elegans/genetics ; Caenorhabditis elegans/growth & development ; Caenorhabditis elegans Proteins/genetics ; Carboxypeptidases/genetics ; Carrier Proteins/genetics ; Cilia/genetics ; Cilia/metabolism ; Glutamic Acid/metabolism ; Humans ; Kinesins/genetics ; Microtubules/genetics ; Mutation/genetics ; NIMA-Related Kinases/genetics ; Nerve Degeneration/genetics ; Nerve Degeneration/pathology ; Neurons/metabolism ; Neurons/pathology ; Peptide Synthases/genetics ; Protein Processing, Post-Translational/genetics ; Tubulin/genetics
    Chemical Substances Caenorhabditis elegans Proteins ; Carrier Proteins ; Tubulin ; Glutamic Acid (3KX376GY7L) ; NIMA-Related Kinases (EC 2.7.11.1) ; Nek10 protein, human (EC 2.7.11.1) ; Carboxypeptidases (EC 3.4.-) ; tubulin deglutamylase, C elegans (EC 3.4.-) ; Kinesins (EC 3.6.4.4) ; Peptide Synthases (EC 6.3.2.-) ; TTLL-4 protein, C elegans (EC 6.3.2.-) ; tyrosyltubulin ligase (EC 6.3.2.-)
    Language English
    Publishing date 2020-10-16
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2186725-2
    ISSN 1553-7404 ; 1553-7390
    ISSN (online) 1553-7404
    ISSN 1553-7390
    DOI 10.1371/journal.pgen.1009052
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: The Prop1-like homeobox gene

    Berghoff, Emily G / Glenwinkel, Lori / Bhattacharya, Abhishek / Sun, HaoSheng / Varol, Erdem / Mohammadi, Nicki / Antone, Amelia / Feng, Yi / Nguyen, Ken / Cook, Steven J / Wood, Jordan F / Masoudi, Neda / Cros, Cyril C / Ramadan, Yasmin H / Ferkey, Denise M / Hall, David H / Hobert, Oliver

    eLife

    2021  Volume 10

    Abstract: Many neuronal identity regulators are expressed in distinct populations of cells in the nervous system, but their function is often analyzed only in specific isolated cellular contexts, thereby potentially leaving overarching themes in gene function ... ...

    Abstract Many neuronal identity regulators are expressed in distinct populations of cells in the nervous system, but their function is often analyzed only in specific isolated cellular contexts, thereby potentially leaving overarching themes in gene function undiscovered. We show here that the
    MeSH term(s) Animals ; Body Patterning/genetics ; Caenorhabditis elegans/embryology ; Caenorhabditis elegans Proteins/genetics ; Caenorhabditis elegans Proteins/metabolism ; Embryo, Nonmammalian/embryology ; Homeodomain Proteins/genetics ; Homeodomain Proteins/metabolism ; Interneurons/physiology ; Motor Neurons/physiology ; Sensory Receptor Cells/physiology ; Synapses/metabolism
    Chemical Substances Caenorhabditis elegans Proteins ; Homeodomain Proteins ; unc-42 protein, C elegans
    Language English
    Publishing date 2021-06-24
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; 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.64903
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Widespread employment of conserved C. elegans homeobox genes in neuronal identity specification.

    Reilly, Molly B / Tekieli, Tessa / Cros, Cyril / Aguilar, G Robert / Lao, James / Toker, Itai Antoine / Vidal, Berta / Leyva-Díaz, Eduardo / Bhattacharya, Abhishek / Cook, Steven J / Smith, Jayson J / Kovacevic, Ismar / Gulez, Burcu / Fernandez, Robert W / Bradford, Elisabeth F / Ramadan, Yasmin H / Kratsios, Paschalis / Bao, Zhirong / Hobert, Oliver

    PLoS genetics

    2022  Volume 18, Issue 9, Page(s) e1010372

    Abstract: Homeobox genes are prominent regulators of neuronal identity, but the extent to which their function has been probed in animal nervous systems remains limited. In the nematode Caenorhabditis elegans, each individual neuron class is defined by the ... ...

    Abstract Homeobox genes are prominent regulators of neuronal identity, but the extent to which their function has been probed in animal nervous systems remains limited. In the nematode Caenorhabditis elegans, each individual neuron class is defined by the expression of unique combinations of homeobox genes, prompting the question of whether each neuron class indeed requires a homeobox gene for its proper identity specification. We present here progress in addressing this question by extending previous mutant analysis of homeobox gene family members and describing multiple examples of homeobox gene function in different parts of the C. elegans nervous system. To probe homeobox function, we make use of a number of reporter gene tools, including a novel multicolor reporter transgene, NeuroPAL, which permits simultaneous monitoring of the execution of multiple differentiation programs throughout the entire nervous system. Using these tools, we add to the previous characterization of homeobox gene function by identifying neuronal differentiation defects for 14 homeobox genes in 24 distinct neuron classes that are mostly unrelated by location, function and lineage history. 12 of these 24 neuron classes had no homeobox gene function ascribed to them before, while in the other 12 neuron classes, we extend the combinatorial code of transcription factors required for specifying terminal differentiation programs. Furthermore, we demonstrate that in a particular lineage, homeotic identity transformations occur upon loss of a homeobox gene and we show that these transformations are the result of changes in homeobox codes. Combining the present with past analyses, 113 of the 118 neuron classes of C. elegans are now known to require a homeobox gene for proper execution of terminal differentiation programs. Such broad deployment indicates that homeobox function in neuronal identity specification may be an ancestral feature of animal nervous systems.
    MeSH term(s) Animals ; Caenorhabditis elegans/genetics ; Caenorhabditis elegans/metabolism ; Caenorhabditis elegans Proteins/metabolism ; Cell Differentiation/genetics ; DNA-Binding Proteins/genetics ; Employment ; Gene Expression Regulation, Developmental ; Genes, Homeobox/genetics ; Neurons/metabolism ; Transcription Factors/genetics ; Transcription Factors/metabolism
    Chemical Substances Caenorhabditis elegans Proteins ; DNA-Binding Proteins ; Transcription Factors
    Language English
    Publishing date 2022-09-30
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2186725-2
    ISSN 1553-7404 ; 1553-7390
    ISSN (online) 1553-7404
    ISSN 1553-7390
    DOI 10.1371/journal.pgen.1010372
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Glutamylation Regulates Transport, Specializes Function, and Sculpts the Structure of Cilia.

    O'Hagan, Robert / Silva, Malan / Nguyen, Ken C Q / Zhang, Winnie / Bellotti, Sebastian / Ramadan, Yasmin H / Hall, David H / Barr, Maureen M

    Current biology : CB

    2017  Volume 27, Issue 22, Page(s) 3430–3441.e6

    Abstract: Ciliary microtubules (MTs) are extensively decorated with post-translational modifications (PTMs), such as glutamylation of tubulin tails. PTMs and tubulin isotype diversity act as a "tubulin code" that regulates cytoskeletal stability and the activity ... ...

    Abstract Ciliary microtubules (MTs) are extensively decorated with post-translational modifications (PTMs), such as glutamylation of tubulin tails. PTMs and tubulin isotype diversity act as a "tubulin code" that regulates cytoskeletal stability and the activity of MT-associated proteins such as kinesins. We previously showed that, in C. elegans cilia, the deglutamylase CCPP-1 affects ciliary ultrastructure, localization of the TRP channel PKD-2 and the kinesin-3 KLP-6, and velocity of the kinesin-2 OSM-3/KIF17, whereas a cell-specific α-tubulin isotype regulates ciliary ultrastructure, intraflagellar transport, and ciliary functions of extracellular vesicle (EV)-releasing neurons. Here we examine the role of PTMs and the tubulin code in the ciliary specialization of EV-releasing neurons using genetics, fluorescence microscopy, kymography, electron microscopy, and sensory behavioral assays. Although the C. elegans genome encodes five tubulin tyrosine ligase-like (TTLL) glutamylases, only ttll-11 specifically regulates PKD-2 localization in EV-releasing neurons. In EV-releasing cephalic male (CEM) cilia, TTLL-11 and the deglutamylase CCPP-1 regulate remodeling of 9+0 MT doublets into 18 singlet MTs. Balanced TTLL-11 and CCPP-1 activity fine-tunes glutamylation to control the velocity of the kinesin-2 OSM-3/KIF17 and kinesin-3 KLP-6 without affecting the intraflagellar transport (IFT) kinesin-II. TTLL-11 is transported by ciliary motors. TTLL-11 and CCPP-1 are also required for the ciliary function of releasing bioactive EVs, and TTLL-11 is itself a novel EV cargo. Therefore, MT glutamylation, as part of the tubulin code, controls ciliary specialization, ciliary motor-based transport, and ciliary EV release in a living animal. We suggest that cell-specific control of MT glutamylation may be a conserved mechanism to specialize the form and function of cilia.
    MeSH term(s) Animals ; Caenorhabditis elegans/metabolism ; Caenorhabditis elegans Proteins/metabolism ; Carboxypeptidases/metabolism ; Cilia/metabolism ; Extracellular Vesicles/metabolism ; Extracellular Vesicles/physiology ; Microtubules/metabolism ; Peptide Synthases/genetics ; Peptide Synthases/metabolism ; Protein Processing, Post-Translational ; Protein Transport/physiology ; Tubulin/metabolism
    Chemical Substances Caenorhabditis elegans Proteins ; Tubulin ; Carboxypeptidases (EC 3.4.-) ; tubulin deglutamylase, C elegans (EC 3.4.-) ; Peptide Synthases (EC 6.3.2.-) ; tubulin polyglutamylase (EC 6.3.2.-) ; tyrosyltubulin ligase (EC 6.3.2.-)
    Language English
    Publishing date 2017-11-09
    Publishing country England
    Document type Journal Article
    ZDB-ID 1071731-6
    ISSN 1879-0445 ; 0960-9822
    ISSN (online) 1879-0445
    ISSN 0960-9822
    DOI 10.1016/j.cub.2017.09.066
    Database MEDical Literature Analysis and Retrieval System OnLINE

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