Induction of glutamine synthetase in embryonic neural retina: localization in Müller fibers and dependence on cell interactions.

Linser, Paul J.; Moscona, A.A.

doi:10.1073/pnas.76.12.6476

Cited by 223 publications

(194 citation statements)

References 28 publications

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“…Cytochemically, Müller glia are amongst the last to express the mature phenotype in many species including zebrafish, and their differentiation is promoted by signaling through the notch pathway (Bernados, et al, 2005;Peterson et al, 2001a;Scheer, et al, 2001). Although cells of the inner nuclear layer are postmitotic by 48 hpf, glutamine synthetase and carbonic anhydrase, two markers of functional Müller glia cells are not detectable until approximately 72 and 96 hpf, respectively, and their expression can be blocked by the pharmacological inhibition of the notch pathway (Bernardos, et al, 2005) consistent with the role of neural glial interactions in Muller cell maturation Moscona, 1979 &.…”

Section: Neurogenesismentioning

confidence: 88%

Zebrafish: A model system for the study of eye genetics

Fadool

Dowling

2008

Progress in Retinal and Eye Research

195

172

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Over the last decade, the use of the zebrafish as a genetic model has moved beyond the proof-ofconcept for the analysis of vertebrate embryonic development to demonstrated utility as a mainstream model organism for the understanding of human disease. The initial identification of a variety of zebrafish mutations affecting the eye and retina, and the subsequent cloning of mutated genes have revealed cellular, molecular and physiological processes fundamental to visual system development. With the increasing development of genetic manipulations, sophisticated techniques for phenotypic characterization, behavioral approaches and screening strategies, the identification of novel genes or novel gene functions will have important implications for our understanding of human eye diseases, pathogenesis, and treatment.

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Section: Neurogenesismentioning

confidence: 88%

Zebrafish: A model system for the study of eye genetics

Fadool

Dowling

2008

Progress in Retinal and Eye Research

195

172

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“…Under normal conditions, amidation of glutamate to glutamine occurs in glial cells, which are the only cells in the retinal tissue that express GS (12,29,30). This could also be the case in injured tissue.…”

Section: Discussionmentioning

confidence: 99%

Glutamine synthetase protects against neuronal degeneration in injured retinal tissue

Gorovits

Avidan

Avisar

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

127

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The neurotransmitter glutamate is neurotoxic when it is accumulated in a massive amount in the extracellular f luid. Excessive release of glutamate has been shown to be a major cause of neuronal degeneration after central nervous system injury. Under normal conditions, accumulation of synaptically released glutamate is prevented, at least in part, by a glial uptake system in which the glia-specific enzyme glutamine synthetase (GS) plays a key role. We postulated that glial cells cannot cope with glutamate neurotoxicity because the level of GS is not high enough to catalyze the excessive amounts of glutamate released by damaged neurons. We examined whether elevation of GS expression in glial cells protects against neuronal degeneration in injured retinal tissue. Analysis of lactate dehydrogenase eff lux, DNA fragmentation, and histological sections revealed that hormonal induction of the endogenous GS gene in retinal glial cells correlates with a decline in neuronal degeneration, whereas inhibition of GS activity by methionine sulfoximine leads to increased cell death. A supply of purified GS enzyme to the culture medium of retinal explants or directly to the embryo in ovo causes a dose-dependent decline in the extent of cell death. These results show that GS is a potent neuroprotectant and that elevation of GS expression in glial cells activates an endogenous mechanism whereby neurons are protected from the deleterious effects of excess glutamate in extracellular f luid after trauma or ischemia. Our results suggest new approaches to the clinical handling of neuronal degeneration.Glutamate neurotoxicity plays an important role in the process of neuronal degeneration after trauma or focal ischemia (for reviews, see refs. 1 and 2). Glutamate, a neurotransmitter that mediates normal excitatory synaptic transmission by interaction with postsynaptic receptors, is neurotoxic when present in excessive amounts. Injured neurons release massive amounts of glutamate, which induce neuronal cell death by continuous overexcitation of postsynaptic receptors. In this way, the initial trauma is amplified and causes the damage to spread to neighboring cells. Under normal conditions, the synaptically released glutamate is taken up into glial cells, where it is converted into glutamine by the glia-specific enzyme glutamine synthetase [GS; L-glutamate:ammonia ligase (ADPforming); EC 6.3.1.2]; glutamine reenters the neurons and is hydrolyzed by glutaminase to form glutamate, thus replenishing the neurotransmitter pool (3, 4). This biochemical pathway fails, however, to prevent glutamate neurotoxicity after insult. We hypothesized that GS is a limiting factor in this process and that its level in glial cells is not high enough to catalyze the excessive amounts of glutamate released by damaged cells. If this is the case, an increase in GS expression should have neuroprotective benefits.To examine the neuroprotective potential of GS, it is necessary to employ an experimental system in which expression of GS can be modulated. The ...

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“…Use of this inhibitor was intended to disrupt the conversion of glutamate to glutamine specifically in retinal Müller cells, which is the cell type in the retina which contains glutamine synthetase (Riepe & Norenberg, 1977,1978Linser & Moscona, 1979), and to impair the recycling scheme (glutamate-glutamine cycle) "in which Müller cells take up released glutamate, convert it to glutamine, and release glutamine as a precursor for neuronal glutamate synthesis into the extracellular space" (Sontheimer, 1995, pg. 123).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, the recycling of the glutamate through Müller cells requires that the glutamate which is taken up be enzymatically converted to glutamine within these cells by glutamine synthetase, which has been localized to Müller cells in the retina (Riepe & Norenberg, 1977,1978Linser & Moscona, 1979). Thus, the high-affinity uptake system, the presence of glutamine synthetase in Müller cells, and the close morphological association of Müller cell processes with photoreceptor synapses (Sarantis & Mobbs, 1992;Pow & Robinson, 1994;Derouiche & Rauen, 1995; but see Lasansky, 1973) are all consistent with a role for the Müller cells in the recycling of glutamate.…”

Section: Introductionmentioning

confidence: 99%

Effects of inhibiting glutamine synthetase and blocking glutamate uptake on b-wave generation in the isolated rat retina

et al. 1999

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The purpose of the present experiments was to evaluate the contribution of the glutamate-glutamine cycle in retinal glial (Müller) cells to photoreceptor cell synaptic transmission. Dark-adapted isolated rat retinas were superfused with oxygenated bicarbonate-buffered media. Recordings were made of the b-wave of the electroretinogram as a measure of light-induced photoreceptor to ON-bipolar neuron transmission. L-methionine sulfoximine (1-10 mM) was added to superfusion media to inhibit glutamine synthetase, a Müller cell specific enzyme, by more than 99% within 5-10 min, thereby disrupting the conversion of glutamate to glutamine in the Müller cells. Threohydroxyaspartic acid and D-aspartate were used to block glutamate transporters. The amplitude of the b-wave was well maintained for 1-2 h provided 0.25 mM glutamate or 0.25 mM glutamine was included in the media. Without exogenous glutamate or glutamine the amplitude of the b-wave declined by about 70% within 1 h. Inhibition of glutamate transporters led to a rapid (2-5 min) reversible loss of the b-wave in the presence and absence of the amino acids. In contrast, inhibition of glutamine synthetase did not alter significantly either the amplitude of the b-wave in the presence of glutamate or glutamine or the rate of decline of the b-wave found in the absence of these amino acids. Excellent recovery of the b-wave was found when 0.25 mM glutamate was resupplied to Lmethionine sulfoximine-treated retinas. The results suggest that in the isolated rat retina uptake of released glutamate into photoreceptors plays a more important role in transmitter recycling than does uptake of glutamate into Müller cells and its subsequent conversion to glutamine.

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Induction of glutamine synthetase in embryonic neural retina: localization in Müller fibers and dependence on cell interactions.

Abstract: The cellular localization of glutamine synthetase [

Cited by 223 publications

References 28 publications

Zebrafish: A model system for the study of eye genetics

Zebrafish: A model system for the study of eye genetics

Glutamine synthetase protects against neuronal degeneration in injured retinal tissue

Effects of inhibiting glutamine synthetase and blocking glutamate uptake on b-wave generation in the isolated rat retina

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