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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 24; pp. 9903 - 9908
• Main Authors: Chowanadisai, Winyoo, Graham, David M., Keen, Carl L., Rucker, Robert B., Messerli, Mark A.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 11.06.2013; National Acad Sciences
• Subjects: Animals; Biological Sciences; Brain; Brain - metabolism; Cation Transport Proteins - genetics; Cation Transport Proteins - metabolism; Cell Line, Tumor; Cell lines; Cells; Cellular differentiation; Chelation; CHO Cells; Cricetinae; Cricetulus; Cyclic AMP Response Element-Binding Protein - genetics; Cyclic AMP Response Element-Binding Protein - metabolism; Embryo, Nonmammalian - embryology; Embryo, Nonmammalian - metabolism; Embryos; Frogs; Gene expression; Gene Expression Profiling; Gene Knockdown Techniques; Humans; Immunoblotting; In Situ Hybridization; Mice; Nervous system; Neurites; Neurites - metabolism; Neurites - physiology; Neurons; Neurulation - genetics; Neurulation - physiology; Oligonucleotide Array Sequence Analysis; Phosphorylation; Polymerization; Reverse Transcriptase Polymerase Chain Reaction; Rodents; Tubulin - genetics; Tubulin - metabolism; Xenopus - embryology; Xenopus - genetics; Xenopus - growth & development; Xenopus Proteins - genetics; Xenopus Proteins - metabolism; Zinc; Zinc - metabolism; brain development; neural tube defect; CREB; birth defects; zinc deficiency
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1222142110

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.