Gestational marginal zinc deficiency impaired fetal neural progenitor cell proliferation by disrupting the ERK1/2 signaling pathway

Nuttall, Johnathan R.; Supasai, Suangsuda; Kha, Jennifer; Vaeth, Brandon M.; Mackenzie, Gerardo G.; Adamo, Ana M.; Oteiza, Patricia I.

doi:10.1016/j.jnutbio.2015.05.007

Cited by 27 publications

(25 citation statements)

References 44 publications

(54 reference statements)

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“…Consistent with our findings of neural cell death, others have shown that reduced zinc conditions lead to cell death of neuroepithelial cells in embryos from wild-type dams given a zincdeficient diet (Dufner-Beattie et al, 2006;Harding et al, 1988), in neuroblastoma and neural progenitor-like cells (Adamo et al, 2010;Nuttall et al, 2015;Seth et al, 2015), in adult neural stem cells (Corniola et al, 2008), and in cortical neurons (Adamo et al, 2010;Ra et al, 2009). Other effects of zinc deficiency include: reduced expression of the neural stem cell marker nestin in embryos and pups from dams fed a severely zinc-deficient diet (Wang et al, 2001); altered neural differentiation of neural precursor cells induced to differentiate with retinoic acid (Morris and Levenson, 2013) and of human induced pluripotent stem cells differentiated to motor neurons (Pfaender et al, 2016); and decreased fetal (rat E19) neural progenitor cell proliferation (Nuttall et al, 2015). Adult mice fed a zinc-deficient diet for 5 weeks show a decrease in proliferating neural cells and immature neurons, and apoptosis in the hippocampus (Gao et al, 2009).…”

Section: Discussion Zinc Is An Essential Nutritional Trace Element Dusupporting

confidence: 92%

“…Our results that include rescue experiments point to p53 as being an important mediator of the apoptotic phenotype, although we are aware that the full response to zinc deficiency is likely molecularly complex and broader than the studies here have covered. Indeed, others have suggested that zinc deficiency alters binding activity of transcription factors involved in neuronal differentiation (Gower-Winter et al, 2013;Morris and Levenson, 2013), and decreases proliferation by reducing ERK1/2 signaling (Nuttall et al, 2015).…”

Section: Zinc Deficiency Disrupts Neural Tube Closure Through P53 Stamentioning

confidence: 99%

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Zinc deficiency causes neural tube defects through attenuation of p53 ubiquitylation

Zhang

Niswander

2018

Development

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Micronutrition is essential for neural tube closure, and zinc deficiency is associated with human neural tube defects. Here, we modeled zinc deficiency in mouse embryos, and used live imaging and molecular studies to determine how zinc deficiency affects neural tube closure. Embryos cultured with the zinc chelator TPEN failed to close the neural tube and showed excess apoptosis. TPEN-induced p53 protein stabilization in vivo and in neuroepithelial cell cultures and apoptosis was dependent on p53. Mechanistically, zinc deficiency resulted in disrupted interaction between p53 and the zinc-dependent E3 ubiquitin ligase Mdm2, and greatly reduced p53 ubiquitylation. Overexpression of human CHIP, a zinc-independent E3 ubiquitin ligase that targets p53, relieved TPEN-induced p53 stabilization and reduced apoptosis. Expression of p53 pro-apoptotic target genes was upregulated by zinc deficiency. Correspondingly, embryos cultured with p53 transcriptional activity inhibitor pifithrin-α could overcome TPEN-induced apoptosis and failure of neural tube closure. Our studies indicate that zinc deficiency disrupts neural tube closure through decreased p53 ubiquitylation, increased p53 stabilization and excess apoptosis.

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Section: Discussion Zinc Is An Essential Nutritional Trace Element Dusupporting

confidence: 92%

Section: Zinc Deficiency Disrupts Neural Tube Closure Through P53 Stamentioning

confidence: 99%

Zinc deficiency causes neural tube defects through attenuation of p53 ubiquitylation

Zhang

Niswander

2018

Development

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“…For example, severe zinc deficiency during early developmental stages is associated with neural tube closure deficits [83,84] and brain malformations. Marginal zinc deficiency during the whole course of pregnancy in turn affects the proliferation of neural progenitor cells, the expression of N-methyl-D-aspartate receptor (NMDAR), and growth and transcription factors which in turn affect the regulation of signaling pathways involved in brain development and function in the offspring of zincdeficient mothers [85][86][87]. If zinc deficiency occurs during postnatal development, pups showed a decreased brain size; reduced brain DNA, RNA, and protein concentrations [88] as well as decreased numbers of neurons and impaired dendritic arborization in the cerebellum of Purkinje, basket, stellate, and granule cells [89][90][91]; and decreased numbers of progenitor cells in the dentate gyrus.…”

Section: Zinc and The Brainmentioning

confidence: 99%

“…Further, in vivo and in vitro studies have shown that zinc deficiency leads to a decrease in progenitor cell proliferation, most likely due to the arrest of the cell cycle whereby cell proliferation is inhibited. In addition, the amount of spontaneous apoptosis is increased under zinc-deficient conditions [87,93,94]. Similarly, knockdown of the zinc transporter Zip12 leads to disturbances in neuronal differentiation affecting neurite sprouting and outgrowth, neurulation, and embryonic development [84].…”

Section: Zinc and The Brainmentioning

confidence: 99%

Zinc Deficiency

Sauer¹,

Hagmeyer²,

Grabrucker³

2016

Nutritional Deficiency

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Zinc is an essential trace element for humans and plays a critical role both as a structural component of proteins and as a cofactor in about 300 enzymes. Zinc deficiency was, for example, reported to affect the immune response and the endocrine system and to induce and modify brain disorders. Besides hereditary zinc deficiency, zinc deficiency-at least in mild forms-is nowadays a very abundant health issue. Today, an estimated 20% of the population worldwide is at risk of developing zinc deficiency with a high number also in industrialized countries. The major risk factors to develop zinc deficiency in industrialized nations are aging and pregnancy. Mechanistic and behavioral studies on the effects of zinc deficiency have mainly been performed using animal models. However, in combination with the few studies on human subjects, a picture emerges that shows importance of adequate nutritional zinc supply for many processes in the body. Especially the immune system and brain development and function seem to be highly sensitive to zinc deficiency. Here, we provide an overview on the effects of zinc deficiency on different organ systems, biological processes, and the associations of zinc deficiency with pathologies observed in humans and animal models.

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“…Gestating and lactating women are the most affected groups [ 4 ], leading to Zn malnutrition in their offspring. This impairs fetal development due to the metal’s involvement in a wide diversity of cellular processes: differentiation, reproduction, metabolism and neurogenesis [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Intrauterine Zn Deficiency Favors Thyrotropin-Releasing Hormone-Increasing Effects on Thyrotropin Serum Levels and Induces Subclinical Hypothyroidism in Weaned Rats

et al. 2017

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Individuals who consume a diet deficient in zinc (Zn-deficient) develop alterations in hypothalamic-pituitary-thyroid axis function, i.e., a low metabolic rate and cold insensitivity. Although those disturbances are related to primary hypothyroidism, intrauterine or postnatal Zn-deficient adults have an increased thyrotropin (TSH) concentration, but unchanged thyroid hormone (TH) levels and decreased body weight. This does not support the view that the hypothyroidism develops due to a low Zn intake. In addition, intrauterine or postnatal Zn-deficiency in weaned and adult rats reduces the activity of pyroglutamyl aminopeptidase II (PPII) in the medial-basal hypothalamus (MBH). PPII is an enzyme that degrades thyrotropin-releasing hormone (TRH). This hypothalamic peptide stimulates its receptor in adenohypophysis, thereby increasing TSH release. We analyzed whether earlier low TH is responsible for the high TSH levels reported in adults, or if TRH release is enhanced by Zn deficiency at weaning. Dams were fed a 2 ppm Zn-deficient diet in the period from one week prior to gestation and up to three weeks after delivery. We found a high release of hypothalamic TRH, which along with reduced MBH PPII activity, increased TSH levels in Zn-deficient pups independently of changes in TH concentration. We found that primary hypothyroidism did not develop in intrauterine Zn-deficient weaned rats and we confirmed that metal deficiency enhances TSH levels since early-life, favoring subclinical hypothyroidism development which remains into adulthood.

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Gestational marginal zinc deficiency impaired fetal neural progenitor cell proliferation by disrupting the ERK1/2 signaling pathway

Cited by 27 publications

References 44 publications

Zinc deficiency causes neural tube defects through attenuation of p53 ubiquitylation

Zinc deficiency causes neural tube defects through attenuation of p53 ubiquitylation

Zinc Deficiency

Intrauterine Zn Deficiency Favors Thyrotropin-Releasing Hormone-Increasing Effects on Thyrotropin Serum Levels and Induces Subclinical Hypothyroidism in Weaned Rats

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