Retinoid X receptors as a potential avenue for regenerative medicine in multiple sclerosis

Huang, Jeffrey K.; Jarjour, Andrew A.; ffrench‐Constant, Charles; Franklin, Robin J.M.

doi:10.1586/ern.11.34

Cited by 11 publications

(11 citation statements)

References 9 publications

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“…We have identified that RARα promotes remyelination. Our findings, together with previous work (Huang et al, 2011), indicate that the RARα/RXR pathway is a promising avenue for remyelination strategies.…”

Section: Discussionsupporting

confidence: 83%

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Regulation of Myelination by Exosome Associated Retinoic Acid Release from NG2-Positive Cells

Goncalves

Clarke

et al. 2019

J. Neurosci.

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In the CNS, oligodendrocytes are responsible for myelin formation and maintenance. Following spinal cord injury, oligodendrocyte loss and an inhibitory milieu compromise remyelination and recovery. Here, we explored the role of retinoic acid receptor-beta (RARβ) signaling in remyelination. Using a male Sprague Dawley rat model of PNS-CNS injury, we show that oral treatment with a novel drug like RARβ agonist, C286, induces neuronal expression of the proteoglycan decorin and promotes myelination and differentiation of oligodendrocyte precursor cells (NG2 + cells) in a decorin-mediated neuron–glia cross talk. Decorin promoted the activation of RARα in NG2 + cells by increasing the availability of the endogenous ligand RA. NG2 + cells synthesize RA, which is released in association with exosomes. We found that decorin prevents this secretion through regulation of the EGFR–calcium pathway. Using functional and pharmacological studies, we further show that RARα signaling is both required and sufficient for oligodendrocyte differentiation. These findings illustrate that RARβ and RARα are important regulators of oligodendrocyte differentiation, providing new targets for myelination. SIGNIFICANCE STATEMENT This study identifies novel therapeutic targets for remyelination after PNS-CNS injury. Pharmacological and knock-down experiments show that the retinoic acid (RA) signaling promotes differentiation of oligodendrocyte precursor cells (OPCs) and remyelination in a cross talk between neuronal RA receptor-beta (RARβ) and RARα in NG2 + cells. We show that stimulation of RARα is required for the differentiation of OPCs and we describe for the first time how oral treatment with a RARβ agonist (C286, currently being tested in a Phase 1 trial, ISRCTN12424734) leads to the endogenous synthesis of RA through retinaldehyde dehydrogenase 2 (Raldh2) in NG2 cells and controls exosome-associated-RA intracellular levels through a decorin–Ca 2+ pathway. Although RARβ has been implicated in distinct aspects of CNS regeneration, this study identifies a novel function for both RARβ and RARα in remyelination.

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Section: Discussionsupporting

confidence: 83%

“…The importance of retinoid signaling in myelination has been previously shown (Huang et al, 2011; Kazakova et al, 2006; Latasa et al, 2010) and has been proposed to be mediated by RXRS (Huang et al, 2011). However, the identification of endogenous ligands for RXRs is contentious (Wolf, 2006; Gilardi and Desvergne, 2014).…”

Section: Discussionmentioning

confidence: 88%

Regulation of Myelination by Exosome Associated Retinoic Acid Release from NG2-Positive Cells

Goncalves

Clarke

et al. 2019

J. Neurosci.

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“…To examine this possibility we performed both viral and pharmacological manipulations in ex vivo cerebellar slice cultures after lysolecithin demyelination, a well-established system for modeling remyelination ex vivo (Birgbauer et al, 2004; Huang et al, 2011). Here, we made cerebellar slices, and treated them with lysolecithin to induce demyelination; 2 days later Daam2-virus (or control) or Sp-8-pCPT-cAMPs (or control) was added (Figures 7A and S6U–S6X).…”

Section: Resultsmentioning

confidence: 99%

Daam2-PIP5K Is a Regulatory Pathway for Wnt Signaling and Therapeutic Target for Remyelination in the CNS

Lee

Chaboub

Zhu

et al. 2015

Neuron

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SUMMARY Wnt signaling plays an essential role in developmental and regenerative myelination of the CNS; however, contributions of proximal regulators of the Wnt receptor complex to these processes remain undefined. To identify components of the Wnt pathway that regulate these processes, we applied a multifaceted discovery platform and found that Daam2-PIP5K comprise a novel pathway regulating Wnt signaling and myelination. Using dorsal patterning of the chick spinal cord we found that Daam2 promotes Wnt signaling and receptor complex formation through PIP5K-PIP2. Analysis of Daam2 function in oligodendrocytes (OLs) revealed that it suppresses OL differentiation during development, after white matter injury (WMI), and is expressed in human white matter lesions. These findings suggest a pharmacological strategy to inhibit Daam2-PIP5K function, application of which stimulates remyelination after WMI. Put together, our studies integrate information from multiple systems to identify a novel regulatory pathway for Wnt signaling and potential therapeutic target for WMI.

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“…Similarly, Ascl-1 expression is increased at the active border of MS lesions, and guides OPC differentiation (Nakatani et al, 2013). Interestingly, the retinoid X receptor γ (RXRγ), a member of the nuclear receptor superfamily that mediates signaling by 9-cis retinoic acid (a vitamin A derivative), has been shown to drive oligodendrocyte differentiation and myelin sheath formation by OPCs (Huang and Franklin, 2012; Huang et al, 2011a,b). Being that RXRγ is highly expressed in acute and remyelinating lesions, RXR agonists have been explored in the pathophysiologic context of MS and shown to improve remyelination in both an ex vivo culture system and in EAE animal models (Diab et al, 2004).…”

Section: Mechanisms Of Tissue Repair and Regenerationmentioning

confidence: 99%

The role of immune cells, glia and neurons in white and gray matter pathology in multiple sclerosis

Mallucci

Peruzzotti-Jametti

Bernstock

et al. 2015

Progress in Neurobiology

128

100

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Multiple sclerosis is one of the most common causes of chronic neurological disability beginning in early to middle adult life. Multiple sclerosis is idiopathic in nature, yet increasing correlative evidence supports a strong association between one’s genetic predisposition, the environment and the immune system. Symptoms of multiple sclerosis have primarily been shown to result from a disruption in the integrity of myelinated tracts within the white matter of the central nervous system. However, recent research has also highlighted the hitherto underappreciated involvement of gray matter in multiple sclerosis disease pathophysiology, which may be especially relevant when considering the accumulation of irreversible damage and progressive disability. This review aims at providing a comprehensive overview of the interplay between inflammation, glial/neuronal damage and regeneration throughout the course of multiple sclerosis via the analysis of both white and gray matter lesional pathology. Further, we describe the common pathological mechanisms underlying both relapsing and progressive forms of multiple sclerosis, and analyze how current (as well as future) treatments may interact and/or interfere with its pathology. Understanding the putative mechanisms that drive disease pathogenesis will be key in helping to develop effective therapeutic strategies to prevent, mitigate, and treat the diverse morbidities associated with multiple sclerosis.

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Retinoid X receptors as a potential avenue for regenerative medicine in multiple sclerosis

Cited by 11 publications

References 9 publications

Regulation of Myelination by Exosome Associated Retinoic Acid Release from NG2-Positive Cells

Regulation of Myelination by Exosome Associated Retinoic Acid Release from NG2-Positive Cells

Daam2-PIP5K Is a Regulatory Pathway for Wnt Signaling and Therapeutic Target for Remyelination in the CNS

The role of immune cells, glia and neurons in white and gray matter pathology in multiple sclerosis

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