Cited by 140Trace Elements in HealthHeavy Metal Exposure and ToxicityNeurogenesis and neuroplasticity mechanisms

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

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Chowanadisai, Winyoo, Graham, David M., Keen, Carl L., Rucker, Robert B., Messerli, Mark A.·2013·Proceedings of the National Academy of Sciences

Abstract

Zn 2+ 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+ , neurulation, and neuronal differentiation.

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  • Deficiencies in maternal zinc during pregnancy can be harmful to fetal development, have been identified as causal in neural tube defects, and may contribute to ASD risk.

    “Deficiencies in maternal zinc during pregnancy can be harmful to fetal development having been identified as causal in neural tube defects and as possibly contributing to ASD risk [168, 169].”

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Authors
Chowanadisai, W., Graham, D. M., Keen, C. L., Rucker, R. B., & Messerli, M. A.
Affiliations
  • Marine Biological Laboratory (US)
  • University of California, Davis (US)
Venue
Proceedings of the National Academy of Sciences
Published
2013-05-28
Volume
110
Issue
24
Pages
9903-9908
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
OpenAlex
W2032713755
Cited by
140
References
37
Citations by year
2026: 5 · 2025: 11 · 2024: 15 · 2023: 11 · 2022: 11 · 2021: 21 · 2020: 17 · 2019: 7 · 2018: 10 · 2017: 9 · 2016: 4 · 2015: 10 · 2014: 8 · 2013: 1
FWCI
7.09
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (P40OD010997)
  • National Institute of General Medical Sciences (P30GM092374)
  • National Center for Research Resources (P41RR001395, P41 RR001395S1)
Topics
  • Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Heavy Metal Exposure and Toxicity
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords
zinc transporters, zinc uptake, neurite outgrowth, neurulation, neural tube closure, neuronal differentiation, CREB phosphorylation, microtubule assembly, brain development, Xenopus tropicalis, N2a cells
MeSH terms
Animals, Brain, Cricetulus, Embryo, Nonmammalian, Cricetinae, Humans, Tubulin, Xenopus, Zinc, Immunoblotting, CHO Cells, Neurites, Cyclic AMP Response Element-Binding Protein, In Situ Hybridization, Reverse Transcriptase Polymerase Chain Reaction, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Cation Transport Proteins, Xenopus Proteins, Cell Line, Tumor, Mice, Neurulation, Gene Knockdown Techniques, Polymerization

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