Loss of Elp3 Impairs the Acetylation and Distribution of Connexin-43 in the Developing Cerebral Cortex

Laguesse, Sophie; Close, Pierre; Hees, Laura Van; Chariot, Alain; Malgrange, Brigitte; Nguyen, Laurent

doi:10.3389/fncel.2017.00122

Cited by 16 publications

(19 citation statements)

References 66 publications

(115 reference statements)

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“…In detail, Elongator-dependent modifications of uridines in the wobble position of tRNA anticodons seem to be of key importance for the fidelity and kinetics of translational elongation, which also guides and directs cotranslational folding dynamics 8 , 9 . Over the past decade, a number of studies have showed that the Elongator complex is involved in various cellular activities that govern the development and maintenance of the nervous system 10 – 14 . Moreover, several studies have linked the occurrence of specific mutations in Elongator subunits with the onset of various neurological disorders 15 – 20 .…”

Section: Introductionmentioning

confidence: 99%

Elongator mutation in mice induces neurodegeneration and ataxia-like behavior

et al. 2018

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Cerebellar ataxias are severe neurodegenerative disorders with an early onset and progressive and inexorable course of the disease. Here, we report a single point mutation in the gene encoding Elongator complex subunit 6 causing Purkinje neuron degeneration and an ataxia-like phenotype in the mutant wobbly mouse. This mutation destabilizes the complex and compromises its function in translation regulation, leading to protein misfolding, proteotoxic stress, and eventual neuronal death. In addition, we show that substantial microgliosis is triggered by the NLRP3 inflammasome pathway in the cerebellum and that blocking NLRP3 function in vivo significantly delays neuronal degeneration and the onset of ataxia in mutant animals. Our data provide a mechanistic insight into the pathophysiology of a cerebellar ataxia caused by an Elongator mutation, substantiating the increasing body of evidence that alterations of this complex are broadly implicated in the onset of a number of diverse neurological disorders.

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Section: Introductionmentioning

confidence: 99%

Elongator mutation in mice induces neurodegeneration and ataxia-like behavior

et al. 2018

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“…In this report, it is indicated that Cx43 favors cell-to-cell contact by interacting with elongator complex elements such as Elp1 and Elp3, allowing the acetylation of Cx43 and its membrane localization (Laguesse, 2017). Such membrane destination of Cx43 dependent on acetylation levels has also been reported in HeLa cells (Laguesse, 2017). An important observation in these studies is that channel activity was not required for neuronal migration.…”

Section: Regulation Of Cell Migration By Connexinsmentioning

confidence: 78%

“…On the other hand, Cx43 favors migration of projection neurons over radial glial cells in the developing brain (Laguesse, 2017). In this report, it is indicated that Cx43 favors cell-to-cell contact by interacting with elongator complex elements such as Elp1 and Elp3, allowing the acetylation of Cx43 and its membrane localization (Laguesse, 2017).…”

Section: Regulation Of Cell Migration By Connexinsmentioning

confidence: 87%

“…Cxs participate in the migration of astrocytes (Homkajorn et al, 2010;Alvarez, 2016;Lagos-Cabre, 2017) and several other cell types, such as neurons (Qi, 2016;Laguesse, 2017), cancer cells (Graeber and Hulser, 1998), keratinocytes (Jaraiz-Rodriguez, 2017) and bone marrow stromal cells (Jin, 2017). Reports have indicated that the mutant Cx26 S17F , related to keratitis-ichthyosis-deafness syndrome (KIDS), reduces GJ communication, and decreases collective migration of primary keratinocytes (Press, 2017).…”

Section: Regulation Of Cell Migration By Connexinsmentioning

confidence: 99%

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Connexins in Astrocyte Migration

et al. 2020

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Astrocytes have long been considered the supportive cells of the central nervous system, but during the last decades, they have gained much more attention because of their active participation in the modulation of neuronal function. For example, after brain damage, astrocytes become reactive and undergo characteristic morphological and molecular changes, such as hypertrophy and increase in the expression of glial fibrillary acidic protein (GFAP), in a process known as astrogliosis. After severe damage, astrocytes migrate to the lesion site and proliferate, which leads to the formation of a glial scar. At this scarforming stage, astrocytes secrete many factors, such as extracellular matrix proteins, cytokines, growth factors and chondroitin sulfate proteoglycans, stop migrating, and the process is irreversible. Although reactive gliosis is a normal physiological response that can protect brain cells from further damage, it also has detrimental effects on neuronal survival, by creating a hostile and non-permissive environment for axonal repair. The transformation of astrocytes from reactive to scar-forming astrocytes highlights migration as a relevant regulator of glial scar formation, and further emphasizes the importance of efficient communication between astrocytes in order to orchestrate cell migration. The coordination between astrocytes occurs mainly through Connexin (Cx) channels, in the form of direct cell-cell contact (gap junctions, GJs) or contact between the extracellular matrix and the astrocytes (hemichannels, HCs). Reactive astrocytes increase the expression levels of several proteins involved in astrocyte migration, such as a v b 3 Integrin, Syndecan-4 proteoglycan, the purinergic receptor P2X7, Pannexin1, and Cx43 HCs. Evidence has indicated that Cx43 HCs play a role in regulating astrocyte migration through the release of small molecules to the extracellular space, which then activate receptors in the same or adjacent cells to continue the signaling cascades required for astrocyte migration. In this review, we describe the communication of astrocytes through Cxs, the role of Cxs in inflammation and astrocyte migration, and discuss the molecular mechanisms that regulate Cx43 HCs, which may provide a therapeutic window of opportunity to control astrogliosis and the progression of neurodegenerative diseases.

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“…We will need to understand if different Elongator subunits and regulatory factors are targets of specific signaling cascades and show cell type specific functions in multicellular organisms (e.g., different neuronal subtypes within the central nervous system). Indeed, recent studies have highlighted the specific involvement of Elongator in the differentiation and migration of only a subset of projection neurons .…”

Section: Discussionmentioning

confidence: 99%

Structural asymmetry in the eukaryotic Elongator complex

et al. 2017

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Edited by Wilhelm JustNucleoside modifications in tRNA anticodons regulate ribosome dynamics during translation elongation and, thereby, fine-tune global protein synthesis rates. The highly conserved eukaryotic Elongator complex conducts specific C5-substitutions in tRNA wobble base uridines. It harbors two copies of each of its six individual subunits, which are all equally important for its activity. Here, we summarize recent developments focusing on the architecture of the Elongator complex, showing an asymmetric subunit arrangement, and its functional implications. In addition, we discuss the role of its proposed active site, its individual subunits and temporarily associated regulatory factors. Finally, we aim to provide mechanistic explanations for the link between mutations in Elongator subunits and the onset of several severe human pathologies.

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Loss of Elp3 Impairs the Acetylation and Distribution of Connexin-43 in the Developing Cerebral Cortex

Cited by 16 publications

References 66 publications

Elongator mutation in mice induces neurodegeneration and ataxia-like behavior

Elongator mutation in mice induces neurodegeneration and ataxia-like behavior

Connexins in Astrocyte Migration

Structural asymmetry in the eukaryotic Elongator complex

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