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.

Public Health Relevance

Peripheral de- and dys-neuropathies are characterized by damage in the myelin sheath, the fatty substance wrapped around the axons that protects them from degeneration. These diseases significantly impact the quality of life of affected patients and caregivers, with high social costs and in the most severe forms, lifespan can be shortened. Currently, no effective treatment is available. Thus, the study of the mechanisms controlling the synthesis of myelin is essential to identify new paths of intervention. We and other groups previously characterized an important growth factor that controls the formation of myelin in the nerves. We also recently showed that other proteins, which act as ?biological scissors?, control the activity of this growth factor. In addition we recently demonstrated that these ?scissors? induce the expression of other molecules, called prostaglandins that promote myelin formation and maintenance in the nerves. By using a combination of cell culture techniques and in vivo animal models, we will investigate how prostaglandins participate in myelin maintenance and axonal preservation. These studies will further elucidate the mechanisms controlling myelination in the nerves and are relevant to develop new therapeutic strategies to promote remyelination in patients affected by peripheral neuropathies.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Cellular and Molecular Biology of Glia Study Section (CMBG)
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Morris, Jill A
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San Raffaele Hospital
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