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

Winyoo Chowanadisai, David M. Graham, Carl L Keen, Robert B. Rucker, Mark A. Messerli

Research output: Contribution to journalArticle

53 Scopus citations

Abstract

Zn2+ is required for many aspects of neuronal structure and function. However, the regulation of Zn2+ 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 themouse and Xenopus nervous system. Mouse neurons and Neuro-2a cells produce fewer and shorter neurites after ZIP12 knockdown without affecting cell viability. Zn2+ 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 cAMPresponse 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 Zn2+ 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 Zn2+ transporter that is specifically required for nervous system development and provides tangible links between Zn2+, neurulation, and neuronal differentiation.

Original languageEnglish (US)
Pages (from-to)9903-9908
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number24
DOIs
StatePublished - Jun 11 2013

Keywords

  • Birth defects
  • Brain development
  • CREB
  • Neural tube defect
  • Zinc deficiency

ASJC Scopus subject areas

  • General

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