Manganese transporter Slc39a14 deficiency revealed its key role in maintaining manganese homeostasis in mice

SLC39A14 (also known as ZIP14), a member of the SLC39A transmembrane metal transporter family, has been reported to mediate the cellular uptake of iron and zinc. Recently, however, mutations in the SLC39A14 gene have been linked to manganese (Mn) accumulation in the brain and childhood-onset parkinsonism dystonia. It has therefore been suggested that SLC39A14 deficiency impairs hepatic Mn uptake and biliary excretion, resulting in the accumulation of Mn in the circulation and brain. To test this hypothesis, we generated and characterized global Slc39a14-knockout (Slc39a14(−/−)) mice and hepatocyte-specific Slc39a14-knockout (Slc39a14(fl/fl);Alb-Cre(+)) mice. Slc39a14(−/−) mice develop markedly increased Mn concentrations in the brain and several extrahepatic tissues, as well as motor deficits that can be rescued by treatment with the metal chelator Na(2)CaEDTA. In contrast, Slc39a14(fl/fl);Alb-Cre(+) mice do not accumulate Mn in the brain or other extrahepatic tissues and do not develop motor deficits, indicating that the loss of Slc39a14 expression selectively in hepatocytes is not sufficient to cause Mn accumulation. Interestingly, Slc39a14(fl/fl);Alb-Cre(+) mice fed a high Mn diet have increased Mn levels in the serum, brain and pancreas, but not in the liver. Taken together, our results indicate that Slc39a14(−/−) mice develop brain Mn accumulation and motor deficits that cannot be explained by a loss of Slc39a14 expression in hepatocytes. These findings provide insight into the physiological role that SLC39A14 has in maintaining Mn homeostasis. Our tissue-specific Slc39a14-knockout mouse model can serve as a valuable tool for further dissecting the organ-specific role of SLC39A14 in regulating the body’s susceptibility to Mn toxicity.