title: Zinc deficiency impairs the renewal of hippocampal neural stem cells in adult rats: involvement of FoxO3a activation and downstream p27(kip1) expression.
abstract: Zinc plays an important role in the development and maintenance of central neural system. Zinc deficiency has been known to alter normal brain function, whose molecular mechanism remains largely elusive. In the present study, we established a zinc deficiency-exposed rat model, and, using western blot and immunohistochemical analyses, found that the expression of FoxO3a and p27(kip1) was remarkably up-regulated in the rat brain hippocampus. Immunofluorescence assay showed that FOXO3a and p27(kip1) were significantly co-localized with nestin, the marker of neural stem cells (NSCs). Furthermore, we identified that the proportion of proliferating NSCs was markedly decreased in zinc-deficient rat hippocampaus. Using C17.2 neural stem cells, it was revealed that exposure to zinc chelator N,N,N',N'-tetrakis-(2-pyridylmethy) ethylenediamine induced the expression of FoxO3a and p27(kip1) , which coincided with reduced NSC proliferation. Furthermore, depletion of FoxO3a inhibited p27(kip1) expression and restored the growth of NSCs. On the basis of these data, we concluded that FoxO3a/p27(kip1) signaling might play a significant role in zinc deficiency-induced growth impairment of NSCs and consequent neurological disorders. We describe here that zinc deficiency induces the proliferative impairment of hippocampal neural stem cells partially through the activation of FOXO3a-p27 axis in rats. Neural progenitor cells exhibited significantly up-regulated expression of FOXO3a and p27 after zinc deficiency in vivo and in vitro. Depletion of FOXO3a ameliorates zinc deficiency-induced expression of p27 and growth impairment of neural stem cells. We provide novel insight into the mechanisms underlying zinc deficiency-induced neurological deficits.
authors.affiliation: Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Department of Occupational Medicine and Environmental Toxicity, School of Public Health, Nantong University, Nantong, Jiangsu Province, China.
authors.forename: Jingling
authors.initials: J
authors.lastname: Han
authors.affiliation: Department of Nutrition and Food hygiene, School of Public Health, Nantong University, Nantong, Jiangsu Province, China.
authors.forename: Jianya
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Department of Occupational Medicine and Environmental Toxicity, School of Public Health, Nantong University, Nantong, Jiangsu Province, China.
authors.forename: Junkang
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Department of Occupational Medicine and Environmental Toxicity, School of Public Health, Nantong University, Nantong, Jiangsu Province, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Ma
authors.affiliation: Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Department of Occupational Medicine and Environmental Toxicity, School of Public Health, Nantong University, Nantong, Jiangsu Province, China.
authors.forename: Xinhang
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Nutrition and Food hygiene, School of Public Health, Nantong University, Nantong, Jiangsu Province, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Wang
authors.affiliation: Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Department of Occupational Medicine and Environmental Toxicity, School of Public Health, Nantong University, Nantong, Jiangsu Province, China.
authors.forename: Shengyang
authors.initials: S
authors.lastname: Jiang
authors.affiliation: Department of Nutrition and Food hygiene, School of Public Health, Nantong University, Nantong, Jiangsu Province, China.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Wan
mesh_terms: D000818:Animals; D002453:Cell Cycle; D002455:Cell Division; D002614:Chelating Agents / Q000494:pharmacology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D005029:Ethylenediamines / Q000494:pharmacology; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology*; D008297:Male; D064231:Nestin / Q000032:analysis; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation; D015032:Zinc / Q000172:deficiency* / Q000502:physiology
chemical_list: C493962:Cdkn1b protein, rat; D002614:Chelating Agents; D005029:Ethylenediamines; C499515:FOXO3 protein, rat; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C577486:Nes protein, rat; D064231:Nestin; D034741:RNA, Small Interfering; D050760:Cyclin-Dependent Kinase Inhibitor p27; D015032:Zinc; C044387:N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine
keywords: FoxO3a; neural stem cells; p27kip1; proliferation; zinc deficiency