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.