Zinc Deficiency Reduces Neurogenesis Accompanied by Neuronal Apoptosis Through Caspase-Dependent and -Independent Signaling Pathways

Gao, Huiling; Zheng, Wei; Xin, Na; Chen, Zhihong; Wang, Zhenyu; Chen, Jie; Wang, Zhan-You

doi:10.1007/s12640-009-9072-7

Cited by 75 publications

(59 citation statements)

References 56 publications

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“…Previous studies have shown that low dietary Zn 2+ intake in rats and mice impairs neurite outgrowth in the brain (26,27). CREB activity and neurite outgrowth are closely linked phases of neuronal differentiation.…”

Section: Discussionmentioning

confidence: 97%

Neurulation and neurite extension require the zinc transporter ZIP12 ( slc39a12 )

Chowanadisai

Graham

Keen

et al. 2013

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

122

153

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Zn2+ is required for many aspects of neuronal structure and function. However, the regulation of Zn 2+ in the nervous system remains poorly understood. Systematic analysis of tissue-profiling microarray data showed that the zinc transporter ZIP12 (slc39a12) is highly expressed in the human brain. In the work reported here, we confirmed that ZIP12 is a Zn 2+ uptake transporter with a conserved pattern of high expression in the mouse and Xenopus nervous system. Mouse neurons and Neuro-2a cells produce fewer and shorter neurites after ZIP12 knockdown without affecting cell viability. Zn 2+ chelation or loading in cells to alter Zn 2+ availability respectively mimicked or reduced the effects of ZIP12 knockdown on neurite outgrowth. ZIP12 knockdown reduces cAMP response element-binding protein activation and phosphorylation at serine 133, which is a critical pathway for neuronal differentiation. Constitutive cAMP response element-binding protein activation restores impairments in neurite outgrowth caused by Zn 2+ chelation or ZIP12 knockdown. ZIP12 knockdown also reduces tubulin polymerization and increases sensitivity to nocodazole following neurite outgrowth. We find that ZIP12 is expressed during neurulation and early nervous system development in Xenopus tropicalis, where ZIP12 antisense morpholino knockdown impairs neural tube closure and arrests development during neurulation with concomitant reduction in tubulin polymerization in the neural plate. This study identifies a Zn 2+ transporter that is specifically required for nervous system development and provides tangible links between Zn 2+

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Section: Discussionmentioning

confidence: 97%

Neurulation and neurite extension require the zinc transporter ZIP12 ( slc39a12 )

Chowanadisai

Graham

Keen

et al. 2013

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

122

153

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“…In comparison to previous studies in adult brain, we found higher levels of zinc in cerebral organoids, although compatible in scale of dosage (Table 2). While higher concentrations of zinc in adult brain are toxic to neural cells and also cause axonal degeneration in mice (47), zinc modulates the proliferation of stem cells and neuronal differentiation during neurogenesis (31)(32)(33). In accordance, previous data from our group have demonstrated increased zinc during neural differentiation of human pluripotent stem cells (48), which may highlight the importance of zinc for the commitment of neural stem cells and justify why levels found in cerebral organoids are subtly higher than those described in the adult brain (Table 2) (9,49,50).…”

Section: Implications Of Trace Elements Detected In Cerebral Organoidmentioning

confidence: 99%

Trace elements during primordial plexiform network formation in human cerebral organoids

Sartore

Cardoso

Lages

et al. 2016

Preprint

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Systematic studies of micronutrients during brain formation are hindered by restrictions to animal models and adult post-mortem tissues. Recently, advances in stem cell biology have enabled recapitulation of the early stages of human telencephalon development. In the present work, we exposed cerebral organoids derived from human pluripotent stem cells to synchrotron radiation in order to measure how biologically valuable micronutrients are incorporated and distributed in the exogenously developing brain. Our findings indicate that elemental inclusion in organoids is consistent with human brain tissue and involves calcium, iron, phosphorus, potassium, sulfur, and zinc. Local trends in concentrations suggest a switch from passive to actively mediated transport across cell membranes. Finally, correlational analysis for pairs of elements shows spatially conserved patterns, suggesting they may physically associate, be stored in similar compartments or used in related biological processes. These findings might reflect which trace elements are important during human brain development and will support studies aimed to unravel the consequences of disrupted metal homeostasis for neurodevelopmental diseases, including those manifested in adulthood.PeerJ Preprints | https://doi.org/10.7287/peerj.preprints.2126v1 | CC BY 4.0 Open Access |

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“…As the period of infancy is most susceptible to dietary zinc deficiency (Sandstead et al, 2000), in the present study, an animal model of maternal zinc deficiency during lactation was used to examine the changes in hippocampal neuronal apoptosis, and the neurotrophic signaling pathways. Previous works have shown that dietary zinc deficiency could cause reduction in hippocampal zinc levels in postnatal and adult rodent brains (Takeda, 2001;Gao et al, 2009). This supports the notion that a reduction in hippocampal zinc is involved in brain dysfunctions, at least partly, caused by neuronal apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Lactational zinc deficiency‐induced hippocampal neuronal apoptosis by a BDNF‐independent TrkB signaling pathway

Gao

Zheng

et al. 2011

Hippocampus

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It is well-known that zinc deficiency leads to neuronal death in the brain. Here we tested the hypothesis that changes in the TrkB signaling pathway are involved in hippocampal neuronal apoptosis of suckling offspring with maternal zinc deficiency. Postpartum mice were fed a zinc-deficient (0.85 ppm) diet and their offspring were used as a lactational zinc deficiency mouse model. At P7, P14, and P21, changes in hippocampal neuronal apoptosis were assessed by Nissl and TUNEL staining. BDNF levels and TrkB neurotrophic signaling were examined using immunoblotting assay. Lactational zinc deficiency resulted in lower levels of p-TrkB and p-ERK, and higher levels of Bax/Bcl-2 and caspase-3 in the hippocampus, suggesting that zinc deficiency-induced low levels of TrkB phosphorylation would abrogate the downstream ERK signaling pathway, leading to hippocampal neuronal apoptosis. Most interestingly, our data showed that the activity of Src, a key molecule for zinc-induced TrkB activation through the BDNF-independent pathway, was inhibited significantly, and the expression levels of BDNF were significantly increased in the hippocampus of suckling mice. The present data indicate that zinc depletion-induced hippocampal neuronal apoptosis is likely through modulation of the TrkB neurotrophic signaling pathway by a BDNF-independent and Src-dependent mechanism, whereas higher expression of BDNF is considered as a protective response, which cannot fully compensate for the injury caused by maternal zinc deficiency.

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Zinc Deficiency Reduces Neurogenesis Accompanied by Neuronal Apoptosis Through Caspase-Dependent and -Independent Signaling Pathways

Cited by 75 publications

References 56 publications

Neurulation and neurite extension require the zinc transporter ZIP12 ( slc39a12 )

Neurulation and neurite extension require the zinc transporter ZIP12 ( slc39a12 )

Trace elements during primordial plexiform network formation in human cerebral organoids

Lactational zinc deficiency‐induced hippocampal neuronal apoptosis by a BDNF‐independent TrkB signaling pathway

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