Zinc inhibits p75NTR-mediated apoptosis in chick neural retina

Allington, C; Shamovsky, Igor L.; Ross, Gregory M.; Riopelle, Richard J.

doi:10.1038/sj.cdd.4400831

Cited by 30 publications

(33 citation statements)

References 49 publications

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“…However, the possibility that Zn has MT-independent effects on the developing brain cannot be overlooked. Zn is not only essential for growth and development but is also involved in antiapoptotic pathways (35)(36)(37). Thus, Zn treatment might promote cell survival, as shown when given with other teratogenic agents (36), to compensate for the alcoholrelated brain disturbances, rather than directly limiting the actions of alcohol.…”

Section: Discussionmentioning

confidence: 99%

Prenatal Zinc Treatment at the Time of Acute Ethanol Exposure Limits Spatial Memory Impairments in Mouse Offspring

2006

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Zinc (Zn) treatment given together with acute ethanol in early pregnancy has previously been demonstrated to protect against physical birth abnormalities in mice. The current study examined whether this Zn treatment (s.c. injection) can also prevent the more subtle cognitive impairments caused by ethanol exposure in early pregnancy. Pregnant C57BL/6J dams were injected with saline (0.85% wt/vol NaCl) or 25% ethanol (0.015 mL/g body weight) intraperitoneally at 0 and 4 h on gestational d (GD) 8. ZnSO 4 (2.5 g Zn/g at 0 h) treatment was administered by s.c. injection immediately following ethanol treatment. Offspring were randomly selected from litters for each of the three treatment groups and were tested at 55 and 70 d of age using a cross-maze water escape task for spatial learning and memory impairments consecutively. No differences were observed between treatments for the spatial learning task. However, young adult mice exposed to ethanol in utero demonstrated impaired spatial memory, with a decrease in correct trials and increased escape latency and incorrect entry measurements, compared with salinetreated controls. In comparison, offspring given s.c. Zn treatment at the time of ethanol exposure were not cognitively impaired, performing at the same level as control mice in the cross-maze escape task. These findings indicate that critically timed Zn administration can limit spatial memory impairments caused by ethanol exposure in early pregnancy. T he teratogenic nature of ethanol has been well documented in humans and experimental animals (1-3). Consumption of ethanol during pregnancy can produce an array of physical abnormalities, including prenatal and/or postnatal growth deficiency and craniofacial dysmorphology (4). However, cognitive and behavioral impairments, such as deficits in attention, learning, and memory (5) are much more commonly observed in children exposed prenatally to ethanol and hence are more significant and costly to both the individual and community. These outcomes result from diverse maternal drinking patterns, ranging from the episodic ЉbingeЉ of large quantities of ethanol over a short time period to chronic ethanol intake.The mechanisms involved in ethanol-related abnormalities are unclear. Although it is likely that many factors are involved, several lines of evidence support fetal Zn deficiency as a major contributing factor to ethanol teratogenicity. First, an adequate supply of Zn to the fetus is critical during pregnancy (6). In rodents, there are similarities in fetal outcome between prenatal Zn deficiency and prenatal ethanol exposure. These include increased fetal resorptions, low birth weight, and birth abnormalities (7-10). These effects are potentiated during organogenesis (GD 7-12 in rodents, weeks 3-9 in humans), a period during early pregnancy critical for development and cell differentiation.Second, studies in rats (11) and in our laboratory using mice demonstrate that acute ethanol exposure in early pregnancy causes fetal Zn deficiency via the induction of ...

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Section: Discussionmentioning

confidence: 99%

Prenatal Zinc Treatment at the Time of Acute Ethanol Exposure Limits Spatial Memory Impairments in Mouse Offspring

2006

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“…Neuronal precursors isolated from the E6 chick retina are susceptible to differentiate in the presence of laminin-1 and insulin (22,23), mimicking the in vivo situation (17,51). Insulin is present in the N2 supplement, and exogenous NGF can induce cell cycle reentry and apoptosis of newborn neurons through p75 NTR (1,17). Dissociated E6 retinal cells obtained as described by Frade et al (20) were suspended in culture medium and plated (20,000 cells/cm 2 ) on 10-mm round glass coverslips in four-well dishes (Greiner Bio-One, Germany).…”

Section: Methodsmentioning

confidence: 99%

Nerve Growth Factor-Induced Cell Cycle Reentry in Newborn Neurons Is Triggered by p38^MAPK-Dependent E2F4 Phosphorylation

Morillo

Abanto

Román

et al. 2012

Molecular and Cellular Biology

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Cumulative evidence indicates that activation of cyclin D-dependent kinase 4/6 (cdk4/6) represents a major trigger of cell cycle reentry and apoptosis in vertebrate neurons. We show here the existence of another mechanism triggering cell cycle reentry in differentiating chick retinal neurons (DCRNs), based on phosphorylation of E2F4 by p38 MAPK . We demonstrate that the activation of p75 NTR by nerve growth factor (NGF) induces nuclear p38 MAPK kinase activity, which leads to Thr phosphorylation and subsequent recruitment of E2F4 to the E2F-responsive cdc2 promoter. Inhibition of p38MAPK , but not of cdk4/6, specifically prevents NGF-dependent cell cycle reentry and apoptosis in DCRNs. Moreover, a constitutively active form of chick E2F4 (Thr261Glu/Thr263Glu) stimulates G 1 /S transition and apoptosis, even after inhibition of p38 MAPK activity. In contrast, a dominant-negative E2F4 form (Thr261Ala/Thr263Ala) prevents NGF-induced cell cycle reactivation and cell death in DCRNs. These results indicate that NGF-induced cell cycle reentry in neurons depends on the activation of a novel, cdk4/6-independent pathway that may participate in neurodegeneration. Neurons have classically been considered as permanently postmitotic cells, but cumulative evidence has challenged this dogma. Several studies have demonstrated that under experimental or pathological conditions, neurons can reactivate the cell cycle, a phenomenon often linked with apoptosis (30). Nevertheless, the molecular mechanism triggering cell cycle reentry in neurons is far from been completely understood. Previous studies have pointed out to the upregulation of cyclin D and the activation of cyclin-dependent kinase 4/6 (cdk4/6) as a trigger for cell cycle reentry and apoptosis in neurons (24,45,60). In this regard, inhibition of cdk4/6 has been shown to protect neurons against apoptosis (61), likely by preventing E2F1 activity in these cells (40). Furthermore, activation of cdk4 in cortical neurons has been shown to induce hyperphosphorylation of the retinoblastoma protein (Rb) family member p130, followed by the release of E2F4 (45), derepression of B-and C-Myb (44), and induction of proapoptotic factor Bim (6). Nevertheless, cell cycle-dependent neuronal death could also be triggered by cyclin D-independent mechanisms. Thus, cell cycle-associated events linked with neurodegeneration in Alzheimer's disease (AD) can be dissociated from classical cell cycle initiation by cyclin D-cdk4/6. While 8% of AD hippocampal neurons have been shown to express nuclear cyclin B in vivo (9), only 0.6% of these neurons express detectable levels of cyclin D (9), mainly present in the cytoplasmic compartment (53). Therefore, cyclin D seems not to participate in cell cycle reactivation in AD.We have demonstrated that cell cycle reentry takes place in differentiating retinal ganglion cells (RGCs) during normal chick retina development (17, 51), a model system that may resemble AD-associated neurodegeneration (19). Cell cycle reentry in differentiating chick retinal neurons (D...

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“…11 Zinc concentrations of 200-5000 mM zinc have also been shown to inhibit p75NTR, TGFb, and Fas receptor-mediated apoptosis. [12][13][14] Additionally, zinc inhibits apoptosis induced through the chemical pathway by etoposide, staurosporine, and microtubule disrupting drugs. [15][16][17][18] These levels of zinc are unlikely to be attained physiologically; rather they are an experimental means to elevate intracellular zinc.…”

Section: Introductionmentioning

confidence: 99%

Zinc inhibits Bax and Bak activation and cytochrome c release induced by chemical inducers of apoptosis but not by death-receptor-initiated pathways

Ganju

Eastman

2003

Cell Death Differ

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Zinc has been known for many years to inhibit apoptosis but the mechanism remains unclear. Originally thought to inhibit an apoptotic endonuclease, zinc has subsequently been shown to inhibit steps earlier in the pathway. Since many additional steps in apoptosis have now been defined, we have re-evaluated the steps inhibited by zinc. In response to activation of the chemical-mediated death pathway by anisomycin, 0.3 mM zinc inhibited Bax and Bak activation, cytochrome c release, and all of the subsequent steps in apoptosis. In the receptor-mediated death pathway initiated by Fas or tumor necrosis factor, 3 mM zinc was required to inhibit apoptosis as judged by inhibition of caspase 3 activity and DNA digestion, but it failed to inhibit cytochrome c release, activation of Bax and Bak, or upstream signaling events in this pathway. These results are consistent with zinc selectively inhibiting activation of BH3-only proteins required in the chemical pathway but inhibiting downstream caspase activation in the death-receptor pathway.

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Zinc inhibits p75NTR-mediated apoptosis in chick neural retina

Cited by 30 publications

References 49 publications

Prenatal Zinc Treatment at the Time of Acute Ethanol Exposure Limits Spatial Memory Impairments in Mouse Offspring

Prenatal Zinc Treatment at the Time of Acute Ethanol Exposure Limits Spatial Memory Impairments in Mouse Offspring

Nerve Growth Factor-Induced Cell Cycle Reentry in Newborn Neurons Is Triggered by p38^MAPK-Dependent E2F4 Phosphorylation

Zinc inhibits Bax and Bak activation and cytochrome c release induced by chemical inducers of apoptosis but not by death-receptor-initiated pathways

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Zinc inhibits p75NTR-mediated apoptosis in chick neural retina

Cited by 30 publications

References 49 publications

Prenatal Zinc Treatment at the Time of Acute Ethanol Exposure Limits Spatial Memory Impairments in Mouse Offspring

Prenatal Zinc Treatment at the Time of Acute Ethanol Exposure Limits Spatial Memory Impairments in Mouse Offspring

Nerve Growth Factor-Induced Cell Cycle Reentry in Newborn Neurons Is Triggered by p38MAPK-Dependent E2F4 Phosphorylation

Zinc inhibits Bax and Bak activation and cytochrome c release induced by chemical inducers of apoptosis but not by death-receptor-initiated pathways

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Nerve Growth Factor-Induced Cell Cycle Reentry in Newborn Neurons Is Triggered by p38^MAPK-Dependent E2F4 Phosphorylation