title: Gestational marginal zinc deficiency impaired fetal neural progenitor cell proliferation by disrupting the ERK1/2 signaling pathway.
abstract: This study investigated if a marginal zinc deficiency during gestation in rats could affect fetal neural progenitor cell (NPC) proliferation through a down-regulation of the extracellular signal-regulated kinase (ERK1/2) signaling pathway. Rats were fed a marginally zinc-deficient or adequate diet from the beginning of gestation until embryonic day (E)19. The proportion of proliferating cells in the E19 fetal ventricular zone was decreased by marginal zinc deficiency. Immunostaining for phosphorylated ERK1/2 in the cerebral cortex was decreased in the marginal zinc fetuses, and this effect was strongest in the ventricular zone. Furthermore, phosphorylation of the upstream mitogen-activated ERK kinases (MEK1/2) was not affected, suggesting that marginal zinc deficiency could have increased ERK-directed phosphatase activity. Similar findings were observed in cultured rat embryonic cortical neurons and in IMR-32 neuroblastoma cells, in which zinc-deficiency decreased ERK1/2 phosphorylation without affecting MEK1/2 phosphorylation. Indeed, zinc deficiency increased the activity of the ERK-directed phosphatase protein phosphatase 2A (PP2A) in the fetal cortex and IMR-32 cells. Inhibition of PP2A with okadaic acid prevented the decrease in ERK phosphorylation and proliferation of zinc-deficient IMR-32 cells. Together these results demonstrated that decreased zinc availability reduces ERK1/2 signaling and decreased NPC proliferation as a consequence of PP2A activation. Disruption of fetal neurogenesis could underlie irreversible neurobehavioral impairments observed after even marginal zinc nutrition during a critical period of early brain development.
authors.affiliation: Departments of Nutrition and Environmental Toxicology, University of California, Davis, One Shields Avenue, Davis, CA 95616, USA.
authors.forename: Johnathan R
authors.initials: JR
authors.lastname: Nuttall
authors.affiliation: Departments of Nutrition and Environmental Toxicology, University of California, Davis, One Shields Avenue, Davis, CA 95616, USA.
authors.forename: Suangsuda
authors.initials: S
authors.lastname: Supasai
authors.affiliation: Departments of Nutrition and Environmental Toxicology, University of California, Davis, One Shields Avenue, Davis, CA 95616, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kha
authors.affiliation: Department of Preventive Medicine, Stony Brook University, Stony Brook, NY 11794-8175, USA.
authors.forename: Brandon M
authors.initials: BM
authors.lastname: Vaeth
authors.affiliation: Department of Preventive Medicine, Stony Brook University, Stony Brook, NY 11794-8175, USA.
authors.forename: Gerardo G
authors.initials: GG
authors.lastname: Mackenzie
authors.affiliation: Department of Biological Chemistry and IQUIFIB (UBA-CONICET), School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Adamo
authors.affiliation: Departments of Nutrition and Environmental Toxicology, University of California, Davis, One Shields Avenue, Davis, CA 95616, USA. Electronic address: poteiza@ucdavis.edu.
authors.forename: Patricia I
authors.initials: PI
authors.lastname: Oteiza
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000196:embryology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D039382:Maternal Nutritional Physiological Phenomena; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D019319:Okadaic Acid / Q000494:pharmacology; D010766:Phosphorylation; D011247:Pregnancy; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D015032:Zinc / Q000172:deficiency*
chemical_list: D019319:Okadaic Acid; D054648:Protein Phosphatase 2; D015032:Zinc
keywords: Cell signaling; Fetal brain development; Keywords; Mineral; Nutrition; Trace element