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

Abstract

Zn2+ 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+

Gestational marginal zinc deficiency impaired fetal neural progenitor cell proliferation by disrupting the ERK1/2 signaling pathway

“…Dietary zinc deficiency decreased BDNF levels in the developing rat brain [39], and a constitutively active form of the cyclic AMP response elementbinding protein (CREB) rescued the decrease in neurite growth resulting from knockdown of the neuronal zinc importer ZIP12 [40]. While ERK1/2 is activated by neurotrophic stimuli, ERK1/2 can also regulate the transcription of BDNF by activating CREB.…”

Differential expression of zinc transporters accompanies the differentiation of C2C12 myoblasts

“…MTF1 in turn promotes the expression of metalloproteases (MMPs) that degrade different components of the extracellular matrix [16–19]. ZIP12 has been found to induce neuronal differentiation via activation of cAMP response element binding protein (CREB) [20]. ZIP14 transports Fe, Mn and Cd in addition to Zn [21–23].…”

Zinc transporter SLC39A10/ZIP10 controls humoral immunity by modulating B-cell receptor signal strength

“…Zn is reported to function as a signaling factor (8)(9)(10)(11) and its homeostasis is tightly controlled by Zn transporters, the SLC39/ZIP and SLC30/ZnT family members, which contribute to Zn influx and efflux, respectively (12,13). Notably, it was shown that Zn transferred by a specific Zn transporter can selectively fine-tune distinct intracellular signaling events (14) by targeting specific signaling molecules (15)(16)(17)(18)(19)(20). Moreover, the disruption of a given Zn signaling axis can have pathogenic consequences in the absence of redundant machinery (21).…”