Liver X receptor β is essential for the differentiation of radial glial cells to oligodendrocytes in the dorsal cortex

Xu, Peng; Xu, Hui; Tang, Xi; Xu, Li; Wang, Y; Guo, Li; Ye, Zhong; Xing, Yan; Wu, Yuzhang; Warner, Margaret; Gustafsson, J; Xia, Fan

doi:10.1038/mp.2014.60

Cited by 46 publications

(37 citation statements)

References 43 publications

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“…In line with the prominent regulatory roles of LXRs in CNS myelination that we demonstrate in the cerebellum, Xu et al showed that LXRβ, by acting on OPC specification in another brain region, the dorsal cortex, is critical for white matter development and CNS myelination, especially in the corpus callosum (19). We provide evidence that LXR isoforms differentially affect CNS myelination.…”

Section: Discussionsupporting

confidence: 58%

Liver X receptors alpha and beta promote myelination and remyelination in the cerebellum

Meffre

Shackleford

Hichor

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The identification of new pathways governing myelination provides innovative avenues for remyelination. Liver X receptors (LXRs) α and β are nuclear receptors activated by oxysterols that originated from the oxidation of cholesterol. They are crucial for cholesterol homeostasis, a major lipid constituent of myelin sheaths that are formed by oligodendrocytes. However, the role of LXRs in myelin generation and maintenance is poorly understood. Here, we show that LXRs are involved in myelination and remyelination processes. LXRs and their ligands are present in oligodendrocytes. We found that mice invalidated for LXRs exhibit altered motor coordination and spatial learning, thinner myelin sheaths, and reduced myelin gene expression. Conversely, activation of LXRs by either 25-hydroxycholesterol or synthetic TO901317 stimulates myelin gene expression at the promoter, mRNA, and protein levels, directly implicating LXRα/β in the transcriptional control of myelin gene expression. Interestingly, activation of LXRs also promotes oligodendroglial cell maturation and remyelination after lysolecithin-induced demyelination of organotypic cerebellar slice cultures. Together, our findings represent a conceptual advance in the transcriptional control of myelin gene expression and strongly support a new role of LXRs as positive modulators in central (re)myelination processes.LXR alpha and beta | oligodendrocytes | cerebellum | myelination | oxysterols

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Section: Discussionsupporting

confidence: 58%

Liver X receptors alpha and beta promote myelination and remyelination in the cerebellum

Meffre

Shackleford

Hichor

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Western blot was performed as described by Xu et al 18. Total protein was extracted from the brain tissues surrounding the hematoma region and at the ipsilateral SN.…”

Section: Methodsmentioning

confidence: 99%

“…The concentration of dopamine in the impaired striatum and ipsilateral substantia nigra (SN) of the ICH mice was measured using high-performance liquid chromatographyelectrochemical detection, as described previously. 18 The chromatographic data were exported and analyzed using ESA software (ESA, Inc). The area under the curve of a standard concentration of dopamine was used to compare the dopamine concentrations in the samples.…”

Section: High-performance Liquid Chromatography-electrochemical Detecmentioning

confidence: 99%

Epothilone B Benefits Nigrostriatal Pathway Recovery by Promoting Microtubule Stabilization After Intracerebral Hemorrhage

Yang

Zhang

et al. 2018

JAHA

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BackgroundMany previous clinical studies have demonstrated that the nigrostriatal pathway, which plays a vital role in movement adjustment, is significantly impaired after stroke, according to medical imaging and autopsies. However, the basic pathomorphological changes have been poorly investigated to date. This study was designed to explore the pathomorphological changes, mechanism, and therapeutic method of nigrostriatal impairment after intracerebral hemorrhage (ICH).Methods and ResultsIntrastriatal injection of autologous blood or microtubule depolymerization reagent nocodazole was performed to mimic the pathology of ICH in C57/BL6 mice. Immunofluorescence, Western blotting, electron microscopy, functional behavioral tests, and anterograde and retrograde neural circuit tracking techniques were used in these mice. The data showed that the number of dopamine neurons and the dopamine concentration were severely decreased and that fine motor function was impaired after ICH. Microtubule depolymerization was the main contributor to the loss of dopamine neurons and to motor function deficits after ICH, as was also proven by intrastriatal injection of nocodazole. Moreover, administration of the microtubule stabilizer epothilone B (1.5 mg/kg) improved the integrity of the nigrostriatal pathway neural circuit, increased the number of dopamine neurons (4598±896 versus 3125±355; P=0.034) and the dopamine concentration (4.28±0.99 versus 3.08±0.75 ng/mg; P=0.041), and enhanced fine motor functional recovery associated with increased acetylated α‐tubulin expression to maintain microtubule stabilization after ICH.ConclusionsOur results clarified the pathomorphological changes of the nigrostriatal pathway after ICH and found that epothilone B helped alleviate nigrostriatal pathway injury after ICH, associated with promoting α‐tubulin acetylation to maintain microtubule stabilization, thus facilitating motor recovery.

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“…LXR knockout mice have reduced myelination in the cerebellum and sciatic nerve, coincident with motor deficits, and LXR activation by the synthetic ligand TO901317 increased expression of myelin-related genes [42,43]. Indeed, loss of LXRβ particularly was found to result in impaired locomotion and decreased myelination in the corpus callosum and optic nerve, and this coincided with a reduction in the differentiation of radial glial cells (RGCs) into oligodendrocyte progenitor cells (OPCs) during development [44]. It has also been observed in vitro that primary oligodendrocytes increase LXRβ expression during differentiation [45], and that the LXR agonist TO901317 stimulates oligodendrocyte differentiation [43], induces LXR target gene expression and mediates cholesterol efflux from oligodendrocytes [45].…”

Section: Lxr Cholesterol Regulation Participates In Myelinationmentioning

confidence: 99%

LXR Regulation of Brain Cholesterol: From Development to Disease

Courtney

Landreth

2016

Trends in Endocrinology & Metabolism

131

105

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Liver X Receptors (LXRs) are master regulators of cholesterol homeostasis and inflammation in the central nervous system (CNS). The brain, which contains a disproportionately large amount of the body's total cholesterol (~25%), requires a complex and delicately balanced cholesterol metabolism to maintain neuronal function. Dysregulation of cholesterol metabolism has been implicated in a number of neurodegenerative diseases including Alzheimer's (AD), Parkinson's (PD), and Huntington's (HD) diseases, among others. Due to their cholesterol sensing and anti-inflammatory activities, LXRs are positioned centrally in the everyday maintenance of central nervous system function. This review will focus on recent research into the role of LXRs in the CNS during normal development and homeostasis and in disease states.

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Liver X receptor β is essential for the differentiation of radial glial cells to oligodendrocytes in the dorsal cortex

Cited by 46 publications

References 43 publications

Liver X receptors alpha and beta promote myelination and remyelination in the cerebellum

Liver X receptors alpha and beta promote myelination and remyelination in the cerebellum

Epothilone B Benefits Nigrostriatal Pathway Recovery by Promoting Microtubule Stabilization After Intracerebral Hemorrhage

LXR Regulation of Brain Cholesterol: From Development to Disease

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