Alternative iron uptake in the peripheral nervous system

MARTINEZ VIVOT R; USACH V; GOITIA B; SETTON PC

Atenas

Congreso; 23rd Biennial Meeting of the ISN-ESN; 2011

Although the molecular identity of the axonal signal that induces the myelinating or non-myelinating phenotype in Schwann cells (SCs) is unknown, there is significant information on the intracellular signals and transcription factors that are involved in the myelination of SCs. Loss of axonal contact in isolated SCs in vitro or after nerve injury in vivo leads to de-differentiation of these cells. Cultured SCs acquire a phenotype similar to SCs precursors and non-myelin forming SCs. We have escribed that holotransferrin (hTf) prevented this de-differentiaton (promoted by serum deprivation), while apotransferrin (aTf) was unable to avoid such effect. Bearing in mind that the only difference between aTf and hTf is iron, we analyzed the effect of the metal on cultured SCs. Recent results from our group show that iron (as ferric ammonium citrate), in the absence of Tf or serum, prevented SCs from de-differentiating. Furthermore, we demonstrated that after iron treatment of SCs, intracellular signals towards differentiation become activated or stabilized through cAMP release, PKA activation and CREB phosphorylation. The prodifferentiating effect of iron and hTf suggests their participation in the axonal signal that occurs during the maturation of SCs, signal that also enables their survival. Whereas Tf-mediated iron uptake is considered the main route of iron uptake in most cells, there is evidence for Tf-independent uptake mechanisms. In the present work we demonstrate the existence of a divalent metal transporter (DMT1) highly described in literature as an iron metabolism key player, but never before within the PNS context. The presence of DMT1 was demonstrated in nerve homogenate, isolated adult-rat myelin and cultured SCs by Western Blot analysis and confirmed through its co-localization with S-100 (SC marker) by immunocytochemistry. Furthermore, the existence of its messenger was verified by RT-PCR both in the contralateral and ipsilateral nerves of rats previously submitted to sciatic nerve crush. Moreover, DMT1 mRNA was found all along the SC progeny (SC precursors (E14), immature SCs (E16, E18, E20) and mature myelinating SCs (P4)). Finally, subcellular localization was assessed and DMT1 presence was demonstrated in the nuclear, mitochondrial, plasma membrane, microsomal and cytosolic fraction of sciatic nerve. These data allow us to confirm the existence of a Tf independent iron uptake mechanism in SCs, validating the role of iron in the axonal signal. Considering that the process of myelination is controlled by this signal, endogenous repair promotion through iron?s prodifferentiating effect could be a promising alternative in the context of demyelinating diseases and remyelinating therapies. Although multiple environmental factors control such repair mechanisms and suggest a certain synergy in cell signaling, these results definitely shed light on the matter.