title: Bexarotene-Activated Retinoid X Receptors Regulate Neuronal Differentiation and Dendritic Complexity.
abstract: Bexarotene-activated retinoid X receptors (RXRs) ameliorate memory deficits in Alzheimer's disease mouse models, including mice expressing human apolipoprotein E (APOE) isoforms. The goal of this study was to gain further insight into molecular mechanisms whereby ligand-activated RXR can affect or restore cognitive functions. We used an unbiased approach to discover genome-wide changes in RXR cistrome (ChIP-Seq) and gene expression profile (RNA-Seq) in response to bexarotene in the cortex of APOE4 mice. Functional categories enriched in both datasets revealed that bexarotene-liganded RXR affected signaling pathways associated with neurogenesis and neuron projection development. To further validate the significance of RXR for these functions, we used mouse embryonic stem (ES) cells, primary neurons, and APOE3 and APOE4 mice treated with bexarotene. In vitro data from ES cells confirmed that bexarotene-activated RXR affected neuronal development at different levels, including proliferation of neural progenitors and neuronal differentiation, and stimulated neurite outgrowth. This effect was validated in vivo by demonstrating an increased number of neuronal progenitors after bexarotene treatment in the dentate gyrus of APOE3 and APOE4 mice. In primary neurons, bexarotene enhanced the dendritic complexity characterized by increased branching, intersections, and bifurcations. This effect was confirmed by in vivo studies demonstrating that bexarotene significantly improved the compromised dendritic structure in the hippocampus of APOE4 mice. We conclude that bexarotene-activated RXRs promote genetic programs involved in the neurogenesis and development of neuronal projections and these results have significance for the improvement of cognitive deficits.
  
  
  CONCLUSIONS
  Bexarotene-activated retinoid X receptors (RXRs) ameliorate memory deficits in Alzheimer's disease mouse models, including mice expressing human apolipoprotein E (APOE) isoforms. The goal of this study was to gain further insight into molecular mechanisms whereby ligand-activated RXR can affect or restore cognitive functions. We used an unbiased approach to discover genome-wide changes in RXR cistrome (ChIP-Seq) and gene expression profile (RNA-Seq) in response to bexarotene in the cortex of APOE4 mice. Functional categories enriched in both datasets revealed that liganded RXR affected signaling pathways associated with neurogenesis and neuron projection development. The significance of RXR for these functions was validated in mouse embryonic stem cells, primary neurons, and APOE3 and APOE4 mice treated with bexarotene.
authors: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, and.
authors: Anais
authors: http://orcid.org/0000-0003-4421-1814
authors: A
authors: Mounier
authors: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, and.
authors: Danko
authors: http://orcid.org/0000-0001-6846-1194
authors: D
authors: Georgiev
authors: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, and.
authors: Kyong Nyon
authors: http://orcid.org/0000-0002-5140-6014
authors: KN
authors: Nam
authors: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, and.
authors: Nicholas F
authors: NF
authors: Fitz
authors: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, and.
authors: Emilie L
authors: EL
authors: Castranio
authors: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, and.
authors: Cody M
authors: http://orcid.org/0000-0003-2874-4944
authors: CM
authors: Wolfe
authors: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, and.
authors: Andrea A
authors: http://orcid.org/0000-0001-8797-3734
authors: AA
authors: Cronican
authors: Institute for Diabetes, Obesity and Metabolism and Functional Genomics Core, Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors: Jonathan
authors: http://orcid.org/0000-0001-6885-7869
authors: J
authors: Schug
authors: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, and iliyal@pitt.edu radak@pitt.edu.
authors: Iliya
authors: I
authors: Lefterov
authors: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, and iliyal@pitt.edu radak@pitt.edu.
authors: Radosveta
authors: R
authors: Koldamova
mesh_terms: D000818:Animals; D000077610:Bexarotene; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D047488:Retinoid X Receptors / Q000819:agonists / Q000378:metabolism*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*
chemical_list: D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; D000077610:Bexarotene
keywords: APOE4 and APOE3; ChIP-Seq/RNA-Seq; adult neurogenesis; bexarotene; neuronal differentiation; retinoid X receptor