MOLECULAR MECHANISMS CONTROLLING PNS MYELIN MAINTENANCE

San Raffaele Hospital, Milano

Investigators

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Abstract

The remarkable interaction between glial cells and axons is crucial for nervous system development and homeostasis. In the PNS, the intimate relationship between axons and Schwann cells (SC) culminates with the production of the myelin sheath, a multilamellar structure that is essential to insulate the axons and ensure efficient propagation of the electric impulse. The importance of the myelin sheath is underscored by the fact that the morbidity associated to disorders of the nervous system affecting myelin formation and/or stability can lead to neuronal cell death. In recent years our understanding of the proteins and the molecular pathways required for the initiation of PNS myelination has significantly increased, however much less is known on the molecules required for the maintenance of the myelin sheath. A key signal for the entire PNS myelination program is Neuregulin 1 (NRG1) type III. We recently demonstrated that NRG1 type III canonical forward signal initiates myelination and regulates the amount of myelin formed, while the backward signal, upregulates the expression of the prostaglandin synthase L-PGDS and activates a novel pathway that is relevant to PNS myelination and maintenance. In the PNS, prostaglandins signal via two different G protein coupled receptor, GPR44 present only in SC and PTGDR that is instead expressed on SC and axons. We showed that GPR44 on SC promotes myelin formation. Our preliminary data indicate that PTGDR instead, transduces signals required for myelin stability. Thus, differential activation of these receptors might trigger distinct, but essential signals required preserving SC - axon communication. We now propose to address fundamental questions to our understanding of the role of prostaglandins in PNS myelin maintenance. Which are the proteins controlled by L-PGDS to promote myelin maintenance? What is the role of PTGDR? Is it really the GPCR transducing ?maintenance? signals? Are GPR44 and PTGDR activating different signaling pathways in SC? We will address these questions by using a combination of in vivo and in vitro experiments and cutting edge technology with the aim of identifying new molecules that can be modulated to restore and/or promote myelination. A characterization of the signaling events involved in myelin maintenance is urgent and has clear translational application, as axonal suffering and neuronal cell death are the main cause of morbidity in patients with progressed demyelinating disorders.