Role of Gap Junction Protein Connexin43 in Astrogliosis Induced by Brain Injury

Theodoric, Nicolas; Bechberger, John F.; Naus, Christian C.; Sin, Wun-Chey

doi:10.1371/journal.pone.0047311

Cited by 60 publications

(64 citation statements)

References 79 publications

(118 reference statements)

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“…63 We previously showed that the upregulation of Cx43 occurs mostly in glial fibrillary acidic protein (GFAP)-expressing reactive astrocytes and not in microglia or NG2 oligodendrocyte progenitors. 19 Reactive astrocytes are one of the major cell types found in gliomas 2,3,64 and they are often indistinguishable from glioma cells in pathological samples. 64 In fact, we observe enhanced Cx43 immunoreactivity only in a sub-population of tumor-associated astrocytes that are closest to the tumor cells.…”

Section: Resultsmentioning

confidence: 99%

“…19 Some evidence suggests that the glial scar acts as a barrier to constrain invasive tumor cells. 73 To determine whether there is a correlation between the extent of astrogliosis and glioma invasiveness, we examined the degree of gliosis by measuring the distance from the tumor periphery to a region of brain parenchyma with no detectable level of GFAP immunoreactivity.…”

Section: Attenuated Glioma Invasion In the Presence Of Truncated Astrmentioning

confidence: 99%

“…[15][16][17] The gap junction protein connexin43 (Cx43) is widely expressed in adult astrocytes 18 and exhibits increased expression in reactive astrocytes induced by various brain pathologies. 19,20 Cx43 belongs to a large family of proteins that form intercellular channels; 21 the docking of two connexin hexamers, or hemichannels, between adjacent cells allows the exchange of small metabolites such as glucose. 22 In addition, gap junction communication has a significant role in intercellular calcium signaling.…”

Section: Introductionmentioning

confidence: 99%

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Astrocytes promote glioma invasion via the gap junction protein connexin43

et al. 2015

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Reactive astrocytes are integral to the glioma microenvironment. Connexin43 (Cx43) is a major gap junction protein in astrocytes and its expression is enhanced significantly in glioma-associated astrocytes, especially at the peri-tumoral region. Although downregulation of Cx43-mediated intercellular communication is associated with increased malignancy in tumor cells, the role of Cx43 in stromal cells in glioma progression is not defined. Using a mouse model consisting of syngeneic intracranial implantation of GL261 glioma cells into Nestin-Cre:Cx43(fl/fl) mice where Cx43 was eliminated in astrocytes, we demonstrate a role of astrocytic Cx43 in the dissemination of glioma cells from the tumor core. To determine whether heterocellular communication between astrocytes and glioma cells is essential for reduced invasion in the absence of astrocytic Cx43, we abolished channel formation between glioma cells and astrocytes by either knocking down Cx43 in glioma cells with short hairpin RNA (shRNA) or overexpressing a dominant-negative channel-defective Cx43-T154A mutant in these cells. Although Cx43shRNA in glioma cells reduced invasion, expression of Cx43-T154A had no effect on glioma invasion, suggesting tumoral Cx43 may influence motility independently from its channel function. Alteration in astrocytic Cx43 function, such as by replacing the wild-type allele with a C-terminal truncated Cx43 mutant exhibiting reduced intercellular coupling, is sufficient to reduce glioma spreading into the brain parenchyma. Our results reveal a novel role of astrocytic Cx43 in the formation of an invasive niche and raise the possibility to control glioma progression by manipulating the microenvironment.

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Section: Resultsmentioning

confidence: 99%

Section: Attenuated Glioma Invasion In the Presence Of Truncated Astrmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Astrocytes promote glioma invasion via the gap junction protein connexin43

et al. 2015

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“…In astrocytes, they are composed of connexins 30 and 43 (Cx30, Cx43) [66]. Cx43 is widely expressed in adult astrocytes and exhibits increased expression in reactive astrocytes induced by various brain pathologies and intercellular calcium signaling [67][68][69][70][71][72][73]. Also, Cx43-mediated intercellular communication between astrocytes plays an important role in the invasion of glioma cells in the brain [63].…”

Section: Astrocytes' Direct Cell-cell Interactions With Tumor Cellsmentioning

confidence: 99%

The Role of Astrocytes in Tumor Growth and Progression

Gronseth¹,

Wang²,

Harder³

et al. 2018

Astrocyte - Physiology and Pathology

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Current research is continually implicating the importance of astrocytes as active participants in neurological injury, disease, and tumor progression. This chapter will discuss some of these emerging concepts, especially as they relate to tumor biology. Astrocytes themselves can become tumorigenic, such as the case in gliomas, which often have aberrant signaling in key regulating genes of astrocyte development. Astrocytes secrete factors that maintain the tight junctions of the blood brain barrier (BBB), which in turn regulates the success or failure of metastatic cells extravasating into the brain. This astrocytic association with the brain vasculature also promotes brain tumor stem cell characteristics, which are known to be necessary for tumor initiation. Tumor cells within the brain make direct contacts with astrocytes through gap junctions, which subsequently lead to increased chemoresistance of the tumor cells. Astrocytes have also been shown to effect tumors cells via secretion of degradative enzymes, cytokines, chemokines, and growth factors, all of which have been shown to promote tumor cell proliferation, survival, and invasion. Thus, research in astrocyte biology and the role of astrocytes in the tumor microenvironment has and will likely continue to reveal novel targets for cancer intervention.

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“…An upregulation or downregulation of Cx43 expression has been observed in reactive astrocytes, while activated microglia are primarily characterized by an induction of Cx43 expression [98,194,[350][351][352][353][354][355][356][357][358][359][360][361]. However, treatments that suppress Cx43-based communication can have different outcomes, i.e., they have been reported to be neuroprotective [337,[362][363][364] as well as neurotoxic [365,366] in different models of neurodegenerative conditions.…”

Section: Contribution Of Astroglial Connexins To Vasomotor Control Anmentioning

confidence: 99%

Connexin and pannexin signaling pathways, an architectural blueprint for CNS physiology and pathology?

Decrock

Bock

Wang

et al. 2015

Cell. Mol. Life Sci.

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The central nervous system (CNS) is composed of a highly heterogeneous population of cells. Dynamic interactions between different compartments (neuronal, glial, and vascular systems) drive CNS function and allow to integrate and process information as well as to respond accordingly. Communication within this functional unit, coined the neuro-glio-vascular unit (NGVU), typically relies on two main mechanisms: direct cell-cell coupling via gap junction channels (GJCs) and paracrine communication via the extracellular compartment, two routes to which channels composed of transmembrane connexin (Cx) or pannexin (Panx) proteins can contribute. Multiple isoforms of both protein families are present in the CNS and each CNS cell type is characterized by a unique Cx/Panx portfolio. Over the last two decades, research has uncovered a multilevel platform via which Cxs and Panxs can influence different cellular functions within a tissue: (1) Cx GJCs enable a direct cell-cell communication of small molecules, (2) Cx hemichannels and Panx channels can contribute to autocrine/paracrine signaling pathways, and (3) different structural domains of these proteins allow for channel-independent functions, such as cell-cell adhesion, interactions with the cytoskeleton, and the activation of intracellular signaling pathways. In this paper, we discuss current knowledge on their multifaceted contribution to brain development and to specific processes in the NGVU, including synaptic transmission and plasticity, glial signaling, vasomotor control, and blood-brain barrier integrity in the mature CNS. By highlighting both physiological and pathological conditions, it becomes evident that Cxs and Panxs can play a dual role in the CNS and that an accurate fine-tuning of each signaling mechanism is crucial for normal CNS physiology.

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Role of Gap Junction Protein Connexin43 in Astrogliosis Induced by Brain Injury

Cited by 60 publications

References 79 publications

Astrocytes promote glioma invasion via the gap junction protein connexin43

Astrocytes promote glioma invasion via the gap junction protein connexin43

The Role of Astrocytes in Tumor Growth and Progression

Connexin and pannexin signaling pathways, an architectural blueprint for CNS physiology and pathology?

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