Liver X Receptors and Oxysterols Promote Ventral Midbrain Neurogenesis In Vivo and in Human Embryonic Stem Cells

Sacchetti, Paola; Sousa, Kyle M.; Hall, Anita; Liste, Isabel; Steffensen, Knut R.; Theofilopoulos, Spyridon; Parish, Clare L.; Hazenberg, Carin; Richter, Lars; Hovatta, Outti; Gustafsson, Jan‐Åke; Arenas, Ernest

doi:10.1016/j.stem.2009.08.019

Cited by 128 publications

(100 citation statements)

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“…This is also true in embryonic brain ( 5 ), but not in the adult, probably because of the predominance of 24S-hydroxycholesterol, which tends to obscure the observation Luciferase assays were performed in the mouse substancia nigra-like cell line SN4741. Both LXR ␣ and -␤ have been shown to be expressed in developing brain ( 58,59 ), and we have previously shown 24S,25-epoxycholesterol, 22R-, 24S-, and 25-hydroxycholesterols to be LXR ligands in this cell line ( 32,58 ). 26-Hydroxycholesterol was not found to be an LXR ligand in this cell line.…”

Section: Discussionmentioning

confidence: 54%

Analysis of bioactive oxysterols in newborn mouse brain by LC/MS

Meljon¹,

Theofilopoulos

Shackleton³

et al. 2012

Journal of Lipid Research

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Section: Discussionmentioning

confidence: 54%

Analysis of bioactive oxysterols in newborn mouse brain by LC/MS

Meljon¹,

Theofilopoulos

Shackleton³

et al. 2012

Journal of Lipid Research

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“…LXR activation promotes synaptic plasticity and axonal regeneration in stroke patients (11) and is required for dopaminergic neuron differentiation, which is useful for Parkinson's disease treatment (4,20). In Alzheimer's disease, LXR activation increases the number of cholinergic neurons and attenuates cognitive impairment by blocking the inflammatory process (12).…”

Section: Discussionmentioning

confidence: 99%

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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“…These two proneural genes are directly or indirectly regulated by, and integrate information from, the ShhFoxa2 and Lmx1a/b-Wnt1-Otx2 networks (Fig. 2, pink, blue and yellow areas), as well as nuclear receptors of the Liver X receptor family (Lxrα/Nr1h3 and Lxrβ/Nr1h2) (Sacchetti et al, 2009) and the morphogen Wnt5a (Andersson et al, 2008) in order to control mDA neurogenesis (Fig. 2, purple area).…”

Section: Da E12mentioning

confidence: 99%

“…These nuclear receptors are ligand-dependent transcription factors that form obligate heterodimers with RXR (retinoid X receptors). LXRs are required to maintain the expression levels of Lmx1b, Wnt1 and Ngn2 in the developing midbrain, and deletion of both Lxr receptors decreased mDA neurogenesis, whereas their overexpression increased it (Sacchetti et al, 2009) (Fig. 2, purple area).…”

Section: Da E12mentioning

confidence: 99%

How to make a midbrain dopaminergic neuron

2015

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Midbrain dopaminergic (mDA) neuron development has been an intense area of research during recent years. This is due in part to a growing interest in regenerative medicine and the hope that treatment for diseases affecting mDA neurons, such as Parkinson's disease (PD), might be facilitated by a better understanding of how these neurons are specified, differentiated and maintained in vivo. This knowledge might help to instruct efforts to generate mDA neurons in vitro, which holds promise not only for cell replacement therapy, but also for disease modeling and drug discovery. In this Primer, we will focus on recent developments in understanding the molecular mechanisms that regulate the development of mDA neurons in vivo, and how they have been used to generate human mDA neurons in vitro from pluripotent stem cells or from somatic cells via direct reprogramming. Current challenges and future avenues in the development of a regenerative medicine for PD will be identified and discussed.

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Liver X Receptors and Oxysterols Promote Ventral Midbrain Neurogenesis In Vivo and in Human Embryonic Stem Cells

Cited by 128 publications

References 50 publications

Analysis of bioactive oxysterols in newborn mouse brain by LC/MS

Analysis of bioactive oxysterols in newborn mouse brain by LC/MS

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

How to make a midbrain dopaminergic neuron

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