Hunter James Kelly Research Institute, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, New York 14203.
Hunter James Kelly Research Institute, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, New York 14203
J Neurosci. 2019 Dec 11;39(50):9940-9953. doi: 10.1523/JNEUROSCI.1409-19.2019. Epub 2019 Nov 1.
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 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 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 -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. 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.
铁是参与髓鞘合成的许多细胞酶的必需辅助因子，铁平衡失调是周围神经病变的核心组成部分。然而，PNS 中的铁吸收和管理还知之甚少。为了研究施旺细胞（SCs）中的铁代谢，我们创建了 3 种可诱导的条件性 KO 小鼠，其中涉及铁摄取和储存的 3 种必需蛋白，二价金属转运蛋白 1（DMT1）、铁蛋白重链（Fth）和转铁蛋白受体 1（Tfr1），在出生后专门在 SC 中被消除。DMT1、Fth 或 Tfr1 的缺失显著降低了 SC 的增殖、成熟和 DRG 轴突的髓鞘形成。这伴随着铁掺入和储存的重要减少。当这些蛋白在出生后第一周被 KO 时，所有 3 种条件性 KO 动物的坐骨神经都显示出髓鞘蛋白合成和髓鞘化轴突百分比的显著减少。Fth 的 KO 产生最严重的表型，其次是 DMT1，最后是 Tfr1。重要的是，DMT1 以及 Fth KO 小鼠表现出明显的运动协调缺陷。相比之下，在成熟的髓鞘形成 SC 中删除这些蛋白导致表型较轻，其特征是髓鞘化轴突的百分比略有减少，以及髓鞘化轴突的 -比率略有变化。这些结果表明，DMT1、Fth 和 Tfr1 是 SC 中早期产后铁摄取和储存的关键蛋白，因此也是 PNS 正常髓鞘形成的关键蛋白。为了确定二价金属转运蛋白 1、转铁蛋白受体 1 和铁蛋白重链在施旺细胞（SC）成熟和髓鞘形成中的功能，我们创建了 3 种条件性 KO 小鼠，在这些小鼠中，这些蛋白在 Sox10 阳性 SC 中被出生后删除。我们已经确定这些蛋白对于正常的 SC 铁摄取和储存是必需的，因此对于 PNS 的有效髓鞘形成是必需的。由于铁对于 SC 成熟是不可或缺的，因此了解 SC 中的铁代谢是开发 PNS 脱髓鞘疾病治疗方法的必要前提。
