DMT1 & Schwann cell differentiation. Evidence for a Tf

MARTINEZ VIVOT, R.; USACH V; GOITIA B; SETTON CP

San Diego, Estados Unidos de Norteamérica

Congreso; 40th annual meeting of the Society for Neuroscience's; 2010

Society for Neuroscience

Schwann cells (SCs) are responsible for the myelination of the peripheral nervous system (PNS). During SCs development, precursors migrate along with the growing axons and proliferate rapidly at postnatal days 2-4 in rats. Loss of axonal contact occurs after nerve injury or in cultured isolated SCs, leading to the downregulation of myelin genes expression such as P0 and MBP. We have previously described that cultured SCs incubated in a serum free medium become de-differentiated, acquiring a phenotype similar to SC precursors and non-myelin forming SCs. Holotransferrin (hTf) prevented the de-differentiation promoted by serum deprivation, while apotransferrin (aTf) was unable to block such effect. This prodifferentiating effect suggests that iron is involved in the physiological axonal signal that occurs during the maturation of SCs and which enables their survival. We have demonstrated that, after iron treatment of SCs, intracellular signals towards differentiation become activated or stabilized through cAMP release, PKA activation and CREB phosphorylation. We have also established that iron modifies the cell’s redox state by augmenting intracellular oxidant species which could be the cause of the signalling pathway previously described. Whereas Tf-mediated iron uptake is considered to be the primary route in most mammalian cells, there is also evidence of Tf independent 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 a rat previously submitted to sciatic nerve crush. Moreover, DMT1 mRNA was found all along the SC progeny, in SC precursors (E14), immature SCs (E16, E18, E20) and mature myelinating SCs (P4). 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. Bearing in mind that the process of myelination is controlled by this signal, endogenous repair promotion through iron’s prodifferentiating effect would 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.