Smoothened/AMP-Activated Protein Kinase Signaling in Oligodendroglial Cell Maturation

Alice Del Giovane,Carola Sposato,Francesco Basoli,Elisabeth Traiffort,Martial Ruat,Alberto Rainer,Antonella Ragnini-Wilson,Abdelmoumen Kassoussi,Linda Tirou,Hélène Faure,Mariagiovanna Russo,Sonia Balestri

doi:10.3389/fncel.2021.801704

Abstract

The regeneration of myelin is known to restore axonal conduction velocity after a demyelinating event. Remyelination failure in the central nervous system contributes to the severity and progression of demyelinating diseases such as multiple sclerosis. Remyelination is controlled by many signaling pathways, such as the Sonic hedgehog (Shh) pathway, as shown by the canonical activation of its key effector Smoothened (Smo), which increases the proliferation of oligodendrocyte precursor cells via the upregulation of the transcription factor Gli1. On the other hand, the inhibition of Gli1 was also found to promote the recruitment of a subset of adult neural stem cells and their subsequent differentiation into oligodendrocytes. Since Smo is also able to transduce Shh signals via various non-canonical pathways such as the blockade of Gli1, we addressed the potential of non-canonical Smo signaling to contribute to oligodendroglial cell maturation in myelinating cells using the non-canonical Smo agonist GSA-10, which downregulates Gli1. Using the Oli-neuM cell line, we show that GSA-10 promotes Gli2 upregulation, MBP and MAL/OPALIN expression via Smo/AMP-activated Protein Kinase (AMPK) signaling, and efficiently increases the number of axonal contact/ensheathment for each oligodendroglial cell. Moreover, GSA-10 promotes the recruitment and differentiation of oligodendroglial progenitors into the demyelinated corpus callosum in vivo. Altogether, our data indicate that non-canonical signaling involving Smo/AMPK modulation and Gli1 downregulation promotes oligodendroglia maturation until axon engagement. Thus, GSA-10, by activation of this signaling pathway, represents a novel potential remyelinating agent.

Highlights

Myelin regeneration or remyelination is a fundamental repair process in the central nervous system (CNS) that is activated during pathological demyelinating events in both animal models of demyelination and humans suffering from multiple sclerosis (MS), the most common demyelinating disease of the CNS
Since GSA-10 belongs to this new class of noncanonical Smo modulators, it was evaluated for its ability to promote MBP expression and Oli-neuM differentiation until axon engagement
Using in vitro and in vivo complementary approaches, we show here that a non-canonical modulator of the Smo receptor, GSA-10, is a potent activator of the maturation of the oligodendroglial cell line Oli-neuM into myelinating cells, and that it promotes the recruitment and differentiation of Olig2+oligodendroglial cells into the demyelinated CNS areas

Summary

Introduction

Myelin regeneration or remyelination is a fundamental repair process in the central nervous system (CNS) that is activated during pathological demyelinating events in both animal models of demyelination and humans suffering from multiple sclerosis (MS), the most common demyelinating disease of the CNS Such spontaneous regenerative responses are observed during. These include the much higher turnover rate of OLs in normal-appearing white matter from MS patients than in the CNS from healthy subjects (Yeung et al, 2019), and identification of NSCs that may be recruited and fated to the oligodendroglial lineage in the human SVZ (Samanta et al, 2015) The recruitment of these various cell subsets in the site of lesion and their respective contribution to the remyelination process remain to be clarified. In addition to the newly generated OPCs, resident OLs appear to participate in remyelination (Franklin and Ffrench-Constant, 2017; Jäkel et al, 2019; Yeung et al, 2019)

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