PMID- 26311769 OWN - NLM STAT- MEDLINE DCOM- 20151124 LR - 20220309 IS - 1529-2401 (Electronic) IS - 0270-6474 (Print) IS - 0270-6474 (Linking) VI - 35 IP - 34 DP - 2015 Aug 26 TI - Bexarotene-Activated Retinoid X Receptors Regulate Neuronal Differentiation and Dendritic Complexity. PG - 11862-76 LID - 10.1523/JNEUROSCI.1001-15.2015 [doi] AB - 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. SIGNIFICANCE STATEMENT: 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. CI - Copyright (c) 2015 the authors 0270-6474/15/3511862-15$15.00/0. FAU - Mounier, Anais AU - Mounier A AUID- ORCID: 0000-0003-4421-1814 AD - Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, and. FAU - Georgiev, Danko AU - Georgiev D AUID- ORCID: 0000-0001-6846-1194 AD - Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, and. FAU - Nam, Kyong Nyon AU - Nam KN AUID- ORCID: 0000-0002-5140-6014 AD - Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, and. FAU - Fitz, Nicholas F AU - Fitz NF AD - Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, and. FAU - Castranio, Emilie L AU - Castranio EL AD - Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, and. FAU - Wolfe, Cody M AU - Wolfe CM AUID- ORCID: 0000-0003-2874-4944 AD - Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, and. FAU - Cronican, Andrea A AU - Cronican AA AUID- ORCID: 0000-0001-8797-3734 AD - Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, and. FAU - Schug, Jonathan AU - Schug J AUID- ORCID: 0000-0001-6885-7869 AD - Institute for Diabetes, Obesity and Metabolism and Functional Genomics Core, Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania 19104. FAU - Lefterov, Iliya AU - Lefterov I AD - Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, and iliyal@pitt.edu radak@pitt.edu. FAU - Koldamova, Radosveta AU - Koldamova R AD - Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, and iliyal@pitt.edu radak@pitt.edu. LA - eng GR - K01AG044490/AG/NIA NIH HHS/United States GR - R01 ES024233/ES/NIEHS NIH HHS/United States GR - K01 AG044490/AG/NIA NIH HHS/United States GR - ES024233/ES/NIEHS NIH HHS/United States GR - AG037919/AG/NIA NIH HHS/United States GR - ES021243/ES/NIEHS NIH HHS/United States GR - AG037481/AG/NIA NIH HHS/United States GR - R01 AG037919/AG/NIA NIH HHS/United States GR - R01 AG037481/AG/NIA NIH HHS/United States GR - R21 ES021243/ES/NIEHS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, U.S. Gov't, Non-P.H.S. PL - United States TA - J Neurosci JT - The Journal of neuroscience : the official journal of the Society for Neuroscience JID - 8102140 RN - 0 (Retinoid X Receptors) RN - 0 (Tetrahydronaphthalenes) RN - A61RXM4375 (Bexarotene) SB - IM MH - Animals MH - Bexarotene MH - Cell Differentiation/drug effects/*physiology MH - Cells, Cultured MH - Dendrites/drug effects/*metabolism MH - Female MH - Humans MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - Neurogenesis/drug effects/*physiology MH - Pregnancy MH - Rats MH - Rats, Sprague-Dawley MH - Retinoid X Receptors/agonists/*metabolism MH - Tetrahydronaphthalenes/*pharmacology PMC - PMC4549399 OTO - NOTNLM OT - APOE4 and APOE3 OT - ChIP-Seq/RNA-Seq OT - adult neurogenesis OT - bexarotene OT - neuronal differentiation OT - retinoid X receptor EDAT- 2015/08/28 06:00 MHDA- 2015/12/15 06:00 PMCR- 2016/02/26 CRDT- 2015/08/28 06:00 PHST- 2015/08/28 06:00 [entrez] PHST- 2015/08/28 06:00 [pubmed] PHST- 2015/12/15 06:00 [medline] PHST- 2016/02/26 00:00 [pmc-release] AID - 35/34/11862 [pii] AID - 1001-15 [pii] AID - 10.1523/JNEUROSCI.1001-15.2015 [doi] PST - ppublish SO - J Neurosci. 2015 Aug 26;35(34):11862-76. doi: 10.1523/JNEUROSCI.1001-15.2015.