Hedgehog Signaling in CNS Remyelination

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1		Xiaofeng Xu	--	2015	2022-08-08 07:33:29	\|
2	format	Jason Zhu	-2 word(s)	2013	2022-08-09 04:22:25	\|

This entry is adapted from the peer-reviewed paper 10.3390/cells11142260

Remyelination is a fundamental repair process in the central nervous system (CNS) that is triggered by demyelinating events. In demyelinating diseases, oligodendrocytes (OLs) are targeted, leading to myelin loss, axonal damage, and severe functional impairment. While spontaneous remyelination often fails in the progression of demyelinating diseases, increased understanding of the mechanisms and identification of targets that regulate myelin regeneration becomes crucial. Several signaling pathways have been implicated in the remyelination process, including the Hedgehog (Hh) signaling pathway.

hedgehog signaling pathway oligodendrocytes remyelination

1. The Promotion of Remyelination by the Hedgehog(Hh) Signaling Pathway

1.1. The Contribution of the Hh Signaling Pathway in Myelination and Remyelination

There exist sequential waves of oligodendrocyte progenitor cells (OPCs) generation in vertebrates, firstly localized in the ventral progenitor domains and later in dorsal regions ^[1]. Although most generated OPCs differentiate into OLs and contribute to myelination, a small fraction of OPCs remain in a low-proliferative or quiescent state in the adult ^[2]. Cell-tracing experiments revealed that most adult OPCs are dorsally-derived in the forebrain ^[3]. After a demyelinating insult, these OPCs undergo activation, proliferation, migration, and differentiation until the formation of new myelin sheaths ^[4]. As mentioned before, NPCs from in the ventricular-subventricular zone (V-SVZ) also can generate OLs after demyelination ^[5]^[6]^[7]^[8].

The contribution of the Shh signaling pathway in the context of CNS demyelination and remyelination has been addressed by several groups. In addition to its early role in the induction of embryonic OPCs ^[9], Shh signaling is also implicated in the generation of postnatal OPC populations ^[10]^[11]. Exogenous Shh is able to increase the OPC population and premyelinating OLs in the adult forebrain ^[12]. Genetic cell-fate labeling experiments revealed that neural stem cells (NSCs) in the dorsal V-SVZ respond to Shh and generate OPCs that come to reside in the corpus callosum. These cells persist into adulthood and contribute to remyelination after Cuprizone-induced demyelination ^[13]. In a model of focal demyelination induced by lysophosphatidyl choline (LPC), the major components of the Hh signaling pathway (including Shh and Smo) were upregulated in the oligodendroglial cells in the area of a lesion. Further gain- and loss-of-function experiments demonstrated that Shh promotes the proliferation and differentiation of OPCs and decreases astrogliosis and macrophage infiltration altogether, leading to the attenuation of the lesion extent during myelin repair ^[14].

The stimulation of Smo activity is compatible with the positive influence that Shh exerts on remyelination. For instance, the microinjection of SAG, a Smo agonist, into the corpus callosum of LPC-induced demyelinated mouse significantly increased OPC proliferation and enhanced remyelination ^[15], in accordance with the recent results in Cuprizone-induced demyelinating models ^[16]. Conversely, GDC-0449 (also referred to as Vismodegib), a specific Smo antagonist, has been reported to repress Gli-mediated transcription in different types of cells ^[17], significantly aggravating disease severity and increasing the extent of demyelination in the EAE model of demyelination ^[18].

Recently, another crucial component of the Hh signaling pathway, the type I transmembrane receptor Boc, was identified as a new regulator of myelin formation and repair ^[19]. During development, Boc forms a Shh receptor with Ptch1 and is necessary for the Shh-mediated proliferation of cerebellar progenitor cells ^[20]. The Boc-null mutant mice displayed delayed myelination, associated with a reduction in callosal axon diameter. In the context of demyelination induced by LPC injection, Boc was significantly up-regulated in the lesion. During myelin repair, Boc mutants exhibit aberrant OPC differentiation, reminiscent of the phenotypes observed after blockade of the Hh signaling pathway.

1.2. Identification of Clobetasol as a Smo agonist for Promoting Remyelination

Although the Hh/Smo signaling pathway possesses an important role in promoting remyelination, the development of related therapeutic strategies has been impeded by the lack of U.S. Food and Drug Administration (FDA)-approved Smo agonists. By using high-throughput screening for cells that express the Smo receptor, four FDA-approved drugs, clobetasol, halcinonide, fluticasone, and flucinonide, were identified as agonists of Smo ^[21]. These drugs have the capacity to bind Smo, promote the internalization of Smo, cause the activation of Gli factors, and increase the proliferation of neuronal progenitor cells. Meanwhile, several bioactive drugs have also been selected in phenotypic screens for their ability to promote MBP expression in different cell-based assays, including primary OPC cultures ^[22]^[23]^[24], mouse OPC cell lines such as Oli-neuM ^[25], and epiblast-derived OPCs ^[26]. These independent drug screens, performed with different libraries and OPC models, support Clobetasol as one of the top-ranking drugs in promoting OPC differentiation and myelin development.

Clobetasol is a member of the glucocorticoid family and is commonly used to treat a number of skin disorders ^[27]. It is a potential remyelinating agent that has been demonstrated to promote the differentiation of OPCs in vitro, as well as remyelination in vivo ^[28]. Najm et al. reported that Clobetasol, as a modulator of the glucocorticoid receptor, specifically promotes rapid myelination in organotypic cerebellar slice cultures, as well as in the CNS of postnatal mouse pups ^[26]. Systematic administration of Clobetasol resulted in a significant increase in newly differentiated OLs and enhanced myelin regeneration in the LPC-induced mouse models of focal demyelination. In an EAE mouse model of chronic progressive MS, an impressive reversal in disease severity was observed when Clobetasol was administrated at the peak of the disease. Furthermore, an assessment of the immune response demonstrated that Clobetasol was able to serve as a robust immunosuppressant in addition to inducing remyelination ^[26]. In addition, Clobetasol enhanced OL production from human OPCs in vitro ^[26]. Neuromyelitis optica (NMO) is a CNS disorder that involves inflammation and demyelination of the spinal cord and optic nerve ^[29]. In a mouse model of NMO produced by an injection of an anti-AQ4 antibody, an intraperitoneal administration of Clobetasol significantly reduced the myelin loss and increased the number of myelinating OLs within the lesions ^[30]. Recent studies further demonstrated that Clobetasol significantly improved NSC survival and prompted the differentiation of NSCs into neurons and OLs while inhibiting astrocyte differentiation, providing a potentially novel mechanism underlying the therapeutic effect of Clobetasol in CNS-related disease ^[31].

Altogether, the identified Smo agonist Clobetasol might function in multiple cell types and act via a range of targets to promote myelin repair. Importantly, Clobetasol is able to pass through the blood–brain barrier, raising the exciting possibility that Clobetasol could advance to clinical trials for the currently unavailable chronic progressive phase of MS.

2. Negative Regulation of Myelination and Remyelination by the Hh Signaling Pathway

2.1. Inhibitory Effect on Myelination by the Hedgehog Signaling

In the transgenic mice that ectopically expressed Shh in the dorsal neural tube, spinal precursor cells were arrested in an undifferentiated state and exhibited elevated levels of proliferation ^[32]. Recently, The team discovered a stage-specific activity of Hh signaling in OL development and showed that persistent activation of Smo in OPCs inhibited their differentiation ^[33]. Thus, Smo-mediated Hh signaling appeared to robustly promote NPC or OPC proliferation and resulted in the inhibition of OPC differentiation and subsequent myelination during early developmental stages. This observation is in agreement with the blockade of myelin development by the Smo agonist, SAG ^[15]. Moreover, the fact that appropriate myelination during development requires down-regulation of Hh is consistent with the thin corpus callosum observed in patients with Gorlin syndrome ^[34]. This syndrome is associated with a mutation in the Hh receptor, Ptch1, that blocks the repression of Smo activity, allowing for the increased activation of Hh signaling. In summary, Smo-mediated Hh signaling has an apparent inhibitory effect on OPC differentiation and developmental myelination.

2.2. Down-Regulation of Gli1 during Myelination and Remyelination

In fact, Gli1, originally considered to be a reliable readout of Hh signaling activity, has proven to be detrimental during myelination and remyelination. During development, the genetic ablation of Gli1 in NPCs appeared to lead to precocious myelination ^[35]. Specifically, the inhibition of Gli1 through specific-inhibitor GANT61 in human iPSCs-derived neural stem cells (NSCs) resulted in the increased generation of OPCs. These GANT61-induced OPCs are more migratory, in agreement with the single-cell RNA sequencing that show up-regulated cytoskeletal reorganization pathways. The differentiated OLs were proven to be functional and able to generate compact myelin both in vitro and in vivo ^[36]. Thus, the inhibition of Gli1 in NSCs facilitates OPC generation and OL maturation during development.

In addition, the negative regulation of myelin regeneration by Gli1 was also reported recently. During the demyelination and remyelination processes, the expression of Gli1 appeared to be variable depending on the animal models that were used. When demyelination was induced in the corpus callosum by an injection of LPC, a relatively moderate transcription of Gli1 was seen in OPCs within the lesions ^[14]. In the EAE model, Gli1 transcription was up-regulated in OPCs and neurons immediately before EAE onset but down-regulated while the demyelination stage ^[37]. Concerning the Cuprizone model, it was noted that little to no up-regulation of Gli1 was observed in the demyelinated corpus callosum, primarily in the reactive astrocytes ^[16]. Importantly, fate-mapping experiments following Cuprizone-induced demyelination showed that a subset of SVZ-derived Gli1-expressing NPCs down-regulated Gli1 expression upon arrival to the lesion site ^[35]. Moreover, the inhibition of Gli1 expression in the Cuprizone model was found to amplify the recruitment of NPCs, promote the migration of OPCs to the demyelinated axons, and enhance remyelination ^[36]^[38]. Concomitantly, the pharmacological inhibition of Gli1 activity directly or indirectly improved the functional outcomes in the EAE model by promoting remyelination and neuroprotection in the spinal cord ^[35].

3. The Complex Involvement of Canonical and Non-Canonical Hedgehog Signaling Pathways in Remyelination

3.1. The Promotion of Remyelination via the Non-Canonical Pathway

As mentioned above, Smo is able to transduce Hh signaling via both canonical and non-canonical pathways ^[39]^[40]^[41]^[42]^[43]^[44]. In agreement with the findings that Gli1 inhibition by GANT61 improves remyelination ^[35], the non-canonical Smo agonist GSA-10 has been recently reported to promote remyelination ^[43]. GSA-10 was first identified through a Smo pharmacophore-based screen ^[45]^[46], and it belongs to a new family of Smo agonists that activate the non-canonical pathways associated with Gli1 inhibition ^[47]. In the Oli-neuM cell line, GSA-10 was a potent activator of OPC differentiation. Upon demyelination induced by LPC, it prompted the OPC recruitment toward the lesion area without enhancing their proliferation. Notably, GSA-10 displayed the ability to promote OL maturation up to the stage of engaging artificial axons ^[43]. In conclusion, non-canonical Hh signaling is able to promote remyelination until axon engagement, representing a novel potential therapeutic target. Thus, together with the remyelinating effects described for the other small molecules binding Smo, the conspicuous remyelinating effects of GSA-10 support the idea that different Smo agonists can activate distinct signaling pathways presumably by activating Smo at different sites ^[42]^[45]^[46]. Interestingly, Smo activation by GSA-10 led to Gli2 upregulation, which is consistent with the recent report that ablation of Gli1 increased the expression of Gli2 in NPCs following Cuprizone-induced demyelination ^[38]. In the same line, Sox17 has also been found to induce OL regeneration in demyelinated areas through an increase in Shh/Smo/Gli2 activity ^[48], further supporting the importance of Gli2 upregulation for the differentiation program under Gli1 downregulation.

3.2. Hh Signaling Modulation Controls Local Inflammatory Cells

Under repairing conditions, inflammatory cells in the affected regions, including astrocytes and microglia, are endowed with beneficial or deleterious properties, promoting or impairing the endogenous capacity of OPCs to induce spontaneous remyelination after myelin loss ^[49]^[50]. Therefore, astrocytes and microglia are becoming additional targets for assessing remyelinating properties afforded by small molecules. The observation that SAG was able to promote OPC differentiation in the context of demyelinated lesions was unexpected given its ability to also promote OPC proliferation ^[15]^[16]. During spontaneous remyelination occurring after LPC-induced demyelination, the Smo receptor is up-regulated in OLs and microglia but at a reduced level in astrocytes. Upon demyelination, SAG might promote the differentiation of OPCs indirectly by influencing microglia, inducing the expression of anti-inflammatory markers. This potential mechanism is supported by the previous report that microglia were shifted to an anti-inflammatory phenotype that could direct OL differentiation during remyelination ^[51]. Consistently, the conditional removal of Smo from microglia resulted in a dramatic decline of differentiated OLs, suggesting that Smo is cell-autonomously required for the response of microglia to a demyelinating event and that the pro-differentiating activity of SAG is related to its influence on microglia. Although GFAP expression did not appear to be regulated by SAG, the selective up-regulation of Smo in astrocytes in the LPC models also raises the possibility that its pro-differentiating activity might be mediated by specific subsets of astrocytes.

References

Kessaris, N.; Fogarty, M.; Iannarelli, P.; Grist, M.; Wegner, M.; Richardson, W.D. Competing waves of oligodendrocytes in the forebrain and postnatal elimination of an embryonic lineage. Nat. Neurosci. 2006, 9, 173–179.
Dawson, M.R.; Polito, A.; Levine, J.M.; Reynolds, R. NG2-expressing glial progenitor cells: An abundant and widespread population of cycling cells in the adult rat CNS. Mol. Cell. Neurosci. 2003, 24, 476–488.
Tripathi, R.B.; Clarke, L.E.; Burzomato, V.; Kessaris, N.; Anderson, P.N.; Attwell, D.; Richardson, W.D. Dorsally and ventrally derived oligodendrocytes have similar electrical properties but myelinate preferred tracts. J. Neurosci. 2011, 31, 6809–6819.
Franklin, R.J.; Gilson, J.M.; Blakemore, W.F. Local recruitment of remyelinating cells in the repair of demyelination in the central nervous system. J. Neurosci. Res. 1997, 50, 337–344.
Menn, B.; Garcia-Verdugo, J.M.; Yaschine, C.; Gonzalez-Perez, O.; Rowitch, D.; Alvarez-Buylla, A. Origin of oligodendrocytes in the subventricular zone of the adult brain. J. Neurosci. 2006, 26, 7907–7918.
Picard-Riera, N.; Decker, L.; Delarasse, C.; Goude, K.; Nait-Oumesmar, B.; Liblau, R.; Pham-Dinh, D.; Baron-Van, E.A. Experimental autoimmune encephalomyelitis mobilizes neural progenitors from the subventricular zone to undergo oligodendrogenesis in adult mice. Proc. Natl. Acad. Sci. USA 2002, 99, 13211–13216.
Cayre, M.; Bancila, M.; Virard, I.; Borges, A.; Durbec, P. Migrating and myelinating potential of subventricular zone neural progenitor cells in white matter tracts of the adult rodent brain. Mol. Cell. Neurosci. 2006, 31, 748–758.
Aguirre, A.; Dupree, J.L.; Mangin, J.M.; Gallo, V. A functional role for EGFR signaling in myelination and remyelination. Nat. Neurosci. 2007, 10, 990–1002.
Traiffort, E.; Zakaria, M.; Laouarem, Y.; Ferent, J. Hedgehog: A key signaling in the development of the oligodendrocyte lineage. J. Dev. Biol 2016, 4, 28.
Tong, C.K.; Fuentealba, L.C.; Shah, J.K.; Lindquist, R.A.; Ihrie, R.A.; Guinto, C.D.; Rodas-Rodriguez, J.L.; Alvarez-Buylla, A. A dorsal SHH-Dependent domain in the V-SVZ produces large numbers of oligodendroglial lineage cells in the postnatal brain. Stem Cell Rep. 2015, 5, 461–470.
Winkler, C.C.; Yabut, O.R.; Fregoso, S.P.; Gomez, H.G.; Dwyer, B.E.; Pleasure, S.J.; Franco, S.J. The dorsal wave of neocortical oligodendrogenesis begins embryonically and requires multiple sources of sonic hedgehog. J. Neurosci. 2018, 38, 5237–5250.
Loulier, K.; Ruat, M.; Traiffort, E. Increase of proliferating oligodendroglial progenitors in the adult mouse brain upon Sonic hedgehog delivery in the lateral ventricle. J. Neurochem. 2006, 98, 530–542.
Sanchez, M.A.; Armstrong, R.C. Postnatal Sonic hedgehog (Shh) responsive cells give rise to oligodendrocyte lineage cells during myelination and in adulthood contribute to remyelination. Exp. Neurol. 2018, 299, 122–136.
Ferent, J.; Zimmer, C.; Durbec, P.; Ruat, M.; Traiffort, E. Sonic Hedgehog signaling is a positive oligodendrocyte regulator during demyelination. J. Neurosci. 2013, 33, 1759–1772.
Laouarem, Y.; Kassoussi, A.; Zahaf, A.; Hutteau-Hamel, T.; Mellouk, A.; Bobe, P.; Mattern, C.; Schumacher, M.; Traiffort, E. Functional cooperation of the hedgehog and androgen signaling pathways during developmental and repairing myelination. Glia 2021, 69, 1369–1392.
Sanchez, M.A.; Sullivan, G.M.; Armstrong, R.C. Genetic detection of Sonic hedgehog (Shh) expression and cellular response in the progression of acute through chronic demyelination and remyelination. Neurobiol. Dis. 2018, 115, 145–156.
Stanton, B.Z.; Peng, L.F. Small-molecule modulators of the Sonic Hedgehog signaling pathway. Mol. Biosyst. 2010, 6, 44–54.
Alvarez, J.I.; Dodelet-Devillers, A.; Kebir, H.; Ifergan, I.; Fabre, P.J.; Terouz, S.; Sabbagh, M.; Wosik, K.; Bourbonniere, L.; Bernard, M.; et al. The Hedgehog pathway promotes blood-brain barrier integrity and CNS immune quiescence. Science 2011, 334, 1727–1731.
Zakaria, M.; Ferent, J.; Hristovska, I.; Laouarem, Y.; Zahaf, A.; Kassoussi, A.; Mayeur, M.E.; Pascual, O.; Charron, F.; Traiffort, E. The Shh receptor Boc is important for myelin formation and repair. Development 2019, 146, dev172502.
Izzi, L.; Levesque, M.; Morin, S.; Laniel, D.; Wilkes, B.C.; Mille, F.; Krauss, R.S.; Mcmahon, A.P.; Allen, B.L.; Charron, F. Boc and Gas1 each form distinct Shh receptor complexes with Ptch1 and are required for Shh-mediated cell proliferation. Dev. Cell 2011, 20, 788–801.
Wang, J.; Lu, J.; Bond, M.C.; Chen, M.; Ren, X.R.; Lyerly, H.K.; Barak, L.S.; Chen, W. Identification of select glucocorticoids as Smoothened agonists: Potential utility for regenerative medicine. Proc. Natl. Acad. Sci. USA 2010, 107, 9323–9328.
Deshmukh, V.A.; Tardif, V.; Lyssiotis, C.A.; Green, C.C.; Kerman, B.; Kim, H.J.; Padmanabhan, K.; Swoboda, J.G.; Ahmad, I.; Kondo, T.; et al. A regenerative approach to the treatment of multiple sclerosis. Nature 2013, 502, 327–332.
Mei, F.; Fancy, S.; Shen, Y.A.; Niu, J.; Zhao, C.; Presley, B.; Miao, E.; Lee, S.; Mayoral, S.R.; Redmond, S.A.; et al. Micropillar arrays as a high-throughput screening platform for therapeutics in multiple sclerosis. Nat. Med. 2014, 20, 954–960.
Lariosa-Willingham, K.D.; Rosler, E.S.; Tung, J.S.; Dugas, J.C.; Collins, T.L.; Leonoudakis, D. A high throughput drug screening assay to identify compounds that promote oligodendrocyte differentiation using acutely dissociated and purified oligodendrocyte precursor cells. BMC Res. Notes 2016, 9, 419.
Porcu, G.; Serone, E.; de Nardis, V.; di Giandomenico, D.; Lucisano, G.; Scardapane, M.; Poma, A.; Ragnini-Wilson, A. Clobetasol and halcinonide act as smoothened agonists to promote myelin gene expression and RxRgamma receptor activation. PLoS ONE 2015, 10, e144550.
Najm, F.J.; Madhavan, M.; Zaremba, A.; Shick, E.; Karl, R.T.; Factor, D.C.; Miller, T.E.; Nevin, Z.S.; Kantor, C.; Sargent, A.; et al. Drug-based modulation of endogenous stem cells promotes functional remyelination in vivo. Nature 2015, 522, 216–220.
Au, W.L.; Skinner, M.F.; Benfeldt, E.; Verbeeck, R.K.; Kanfer, I. Application of dermal microdialysis for the determination of bioavailability of clobetasol propionate applied to the skin of human subjects. Skin Pharmacol. Physiol. 2012, 25, 17–24.
Lubetzki, C.; Zalc, B.; Williams, A.; Stadelmann, C.; Stankoff, B. Remyelination in multiple sclerosis: From basic science to clinical translation. Lancet Neurol. 2020, 19, 678–688.
Wu, Y.; Zhong, L.; Geng, J. Neuromyelitis optica spectrum disorder: Pathogenesis, treatment, and experimental models. Mult. Scler. Relat. Disord. 2019, 27, 412–418.
Yao, X.; Su, T.; Verkman, A.S. Clobetasol promotes remyelination in a mouse model of neuromyelitis optica. Acta Neuropathol. Commun. 2016, 4, 42.
Shi, W.; Bi, S.; Dai, Y.; Yang, K.; Zhao, Y.; Zhang, Z. Clobetasol propionate enhances neural stem cell and oligodendrocyte differentiation. Exp. Ther. Med. 2019, 18, 1258–1266.
Rowitch, D.H.; S-Jacques, B.; Lee, S.M.; Flax, J.D.; Snyder, E.Y.; Mcmahon, A.P. Sonic hedgehog regulates proliferation and inhibits differentiation of CNS precursor cells. J. Neurosci. 1999, 19, 8954–8965.
Xu, X.; Yu, Q.; Fang, M.; Yi, M.; Yang, A.; Xie, B.; Yang, J.; Zhang, Z.; Dai, Z.; Qiu, M. Stage-specific regulation of oligodendrocyte development by Hedgehog signaling in the spinal cord. Glia 2020, 68, 422–434.
Kantarci, M.; Ertas, U.; Alper, F.; Sutbeyaz, Y.; Karasen, R.M.; Onbas, O. Gorlin’s syndrome with a thin corpus callosum and a third ventricular cyst. Neuroradiology 2003, 45, 390–392.
Samanta, J.; Grund, E.M.; Silva, H.M.; Lafaille, J.J.; Fishell, G.; Salzer, J.L. Inhibition of Gli1 mobilizes endogenous neural stem cells for remyelination. Nature 2015, 526, 448–452.
Namchaiw, P.; Wen, H.; Mayrhofer, F.; Chechneva, O.; Biswas, S.; Deng, W. Temporal and partial inhibition of GLI1 in neural stem cells (NSCs) results in the early maturation of NSC derived oligodendrocytes in vitro. Stem Cell Res. Ther. 2019, 10, 272.
Wang, Y.; Imitola, J.; Rasmussen, S.; O’Connor, K.C.; Khoury, S.J. Paradoxical dysregulation of the neural stem cell pathway sonic hedgehog-Gli1 in autoimmune encephalomyelitis and multiple sclerosis. Ann. Neurol. 2008, 64, 417–427.
Radecki, D.Z.; Messling, H.M.; Haggerty-Skeans, J.R.; Bhamidipati, S.K.; Clawson, E.D.; Overman, C.A.; Thatcher, M.M.; Salzer, J.L.; Samanta, J. Relative levels of gli1 and gli2 determine the response of ventral neural stem cells to demyelination. Stem Cell Reports 2020, 15, 1047–1055.
Yam, P.T.; Charron, F. Signaling mechanisms of non-conventional axon guidance cues: The Shh, BMP and Wnt morphogens. Curr. Opin. Neurobiol. 2013, 23, 965–973.
Ruat, M.; Hoch, L.; Faure, H.; Rognan, D. Targeting of Smoothened for therapeutic gain. Trends Pharmacol. Sci. 2014, 35, 237–246.
Ferent, J.; Traiffort, E. Hedgehog: Multiple paths for multiple roles in shaping the brain and spinal cord. Neuroscientist 2015, 21, 356–371.
Akhshi, T.; Trimble, W.S. A non-canonical Hedgehog pathway initiates ciliogenesis and autophagy. J. Cell Biol. 2021, 220, e202004179.
Del Giovane, A.; Russo, M.; Tirou, L.; Faure, H.; Ruat, M.; Balestri, S.; Sposato, C.; Basoli, F.; Rainer, A.; Kassoussi, A.; et al. Smoothened/AMP-Activated protein kinase signaling in oligodendroglial cell maturation. Front. Cell. Neurosci. 2021, 15, 801704.
Schmidt-Heck, W.; Matz-Soja, M.; Aleithe, S.; Marbach, E.; Guthke, R.; Gebhardt, R. Fuzzy modeling reveals a dynamic self-sustaining network of the GLI transcription factors controlling important metabolic regulators in adult mouse hepatocytes. Mol. Biosyst. 2015, 11, 2190–2197.
Gorojankina, T.; Hoch, L.; Faure, H.; Roudaut, H.; Traiffort, E.; Schoenfelder, A.; Girard, N.; Mann, A.; Manetti, F.; Solinas, A.; et al. Discovery, molecular and pharmacological characterization of GSA-10, a novel small-molecule positive modulator of Smoothened. Mol. Pharmacol. 2013, 83, 1020–1029.
Fleury, A.; Hoch, L.; Martinez, M.C.; Faure, H.; Taddei, M.; Petricci, E.; Manetti, F.; Girard, N.; Mann, A.; Jacques, C.; et al. Hedgehog associated to microparticles inhibits adipocyte differentiation via a non-canonical pathway. Sci Rep. 2016, 6, 23479.
Manetti, F.; Petricci, E.; Gabrielli, A.; Mann, A.; Faure, H.; Gorojankina, T.; Brasseur, L.; Hoch, L.; Ruat, M.; Taddei, M. Design, synthesis and biological characterization of a new class of osteogenic (1H)-quinolone derivatives. Eur. J. Med. Chem. 2016, 121, 747–757.
Ming, X.; Dupree, J.L.; Gallo, V.; Chew, L.J. Sox17 promotes oligodendrocyte regeneration by dual modulation of hedgehog and wnt signaling. iScience 2020, 23, 101592.
Franklin, R.J.M.; Ffrench-Constant, C. Regenerating CNS myelin—From mechanisms to experimental medicines. Nat. Rev. Neurosci. 2017, 18, 753–769.
Traiffort, E.; Kassoussi, A.; Zahaf, A.; Laouarem, Y. Astrocytes and microglia as major players of myelin production in normal and pathological conditions. Front. Cell. Neurosci. 2020, 14, 79.
Miron, V.E. M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat. Neurosci. 2013, 16, 1211–1218.

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