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Iron is an essential cofactor for many cellular enzymes involved in myelin synthesis, and iron homeostasis unbalance is a central component of peripheral neuropathies. However, iron absorption and management in the PNS are poorly understood. To study iron metabolism in Schwann cells (SCs), we have created 3 inducible conditional KO mice in which three essential proteins implicated in iron uptake and storage, the divalent metal transporter 1 (DMT1), the ferritin heavy chain (Fth), and the transferrin receptor 1 (Tfr1), were postnatally ablated specifically in SCs. Deleting DMT1, Fth, or Tfr1 in vitro significantly reduce SC proliferation, maturation, and the myelination of DRG axons. This was accompanied by an important reduction in iron incorporation and storage. When these proteins were KO in vivo during the first postnatal week, the sciatic nerve of all 3 conditional KO animals displayed a significant reduction in the synthesis of myelin proteins and in the percentage of myelinated axons. Knocking out Fth produced the most severe phenotype, followed by DMT1 and, last, Tfr1. Importantly, DMT1 as well as Fth KO mice showed substantial motor coordination deficits. In contrast, deleting these proteins in mature myelinating SCs results in milder phenotypes characterized by small reductions in the percentage of myelinated axons and minor changes in the g -ratio of myelinated axons. These results indicate that DMT1, Fth, and Tfr1 are critical proteins for early postnatal iron uptake and storage in SCs and, as a consequence, for the normal myelination of the PNS. SIGNIFICANCE STATEMENT To determine the function of the divalent metal transporter 1, the transferrin receptor 1, and the ferritin heavy chain in Schwann cell (SC) maturation and myelination, we created 3 conditional KO mice in which these proteins were postnatally deleted in Sox10-positive SCs. We have established that these proteins are necessary for normal SC iron incorporation and storage, and, as a consequence, for an effective myelination of the PNS. Since iron is indispensable for SC maturation, understanding iron metabolism in SCs is an essential prerequisite for developing therapies for demyelinating diseases in the PNS.

Iron Metabolism in the Peripheral Nervous System: The Role of DMT1, Ferritin, and Transferrin Receptor in Schwann Cell Maturation and Myelination