title: Estrogen receptor (ER) β expression in oligodendrocytes is required for attenuation of clinical disease by an ERβ ligand.
abstract: Treatment of experimental autoimmune encephalomyelitis (EAE) mice with the estrogen receptor (ER) β ligand diarylpropionitrile (DPN) has been shown to have neuroprotective effects via stimulation of endogenous myelination. The direct cellular mechanisms underlying the effects of this ERβ ligand on the central nervous system are uncertain because different cell types in both the peripheral immune system and central nervous system express ERs. ERβ is the target molecule of DPN because DPN treatment fails to decrease EAE clinical symptoms in global ERβ-null mice. Here we investigated the potential role of ERβ expression in cells of oligodendrocyte (OL) lineage in ERβ ligand-mediated neuroprotection. To this end, we selectively deleted ERβ in OLs using the well-characterized Cre-loxP system for conditional gene knockout (CKO) in mice. The effects of this ERβ CKO on ERβ ligand-mediated neuroprotective effects in chronic EAE mice were investigated. ERβ CKO in OLs prevented DPN-induced decrease in EAE clinical disease. DPN treatment during EAE did not attenuate demyelination, only partially improved axon conduction, and did not activate the phosphatidylinositol 3-kinase/serine-threonine-specific protein kinase/mammalian target of rapamycin signaling pathway in ERβ CKO mice. However, DPN treatment significantly increased brain-derived neurotrophic factor levels in ERβ CKO mice. These findings demonstrate that signaling through ERβ in OLs is essential for the beneficial myelination effects of the ERβ ligand DPN in chronic EAE mice. Further, these findings have important implications for neuroprotective therapies that directly target OL survival and myelination.
authors.affiliation: Multiple Sclerosis Program, Department of Neurology, Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience, and Brain Research Institute, David Geffen School of Medicine, University of California, Los Angeles, CA 90095.
authors.forename: Anna J
authors.initials: AJ
authors.lastname: Khalaj
authors.forename: Jaehee
authors.initials: J
authors.lastname: Yoon
authors.forename: Jaspreet
authors.initials: J
authors.lastname: Nakai
authors.forename: Zachary
authors.initials: Z
authors.lastname: Winchester
authors.forename: Spencer M
authors.initials: SM
authors.lastname: Moore
authors.forename: Timothy
authors.initials: T
authors.lastname: Yoo
authors.forename: Leonardo
authors.initials: L
authors.lastname: Martinez-Torres
authors.forename: Shalini
authors.initials: S
authors.lastname: Kumar
authors.forename: Noriko
authors.initials: N
authors.lastname: Itoh
authors.forename: Seema Kaushalya
authors.initials: SK
authors.lastname: Tiwari-Woodruff
mesh_terms: D000818:Animals; D019070:Cell Lineage / Q000502:physiology; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000378:metabolism*; D009186:Myelin Sheath / Q000187:drug effects; D009570:Nitriles / Q000378:metabolism / Q000494:pharmacology*; D009836:Oligodendroglia / Q000378:metabolism*; D011422:Propionates / Q000378:metabolism / Q000494:pharmacology*; D013116:Spinal Cord / Q000473:pathology
chemical_list: C486182:2,3-bis(4-hydroxyphenyl)-propionitrile; D047629:Estrogen Receptor beta; D009570:Nitriles; D011422:Propionates
keywords: differentiation; proliferation; remyelination