title: Unexpected central role of the androgen receptor in the spontaneous regeneration of myelin.
abstract: Lost myelin can be replaced after injury or during demyelinating diseases in a regenerative process called remyelination. In the central nervous system (CNS), the myelin sheaths, which protect axons and allow the fast propagation of electrical impulses, are produced by oligodendrocytes. The abundance and widespread distribution of oligodendrocyte progenitors (OPs) within the adult CNS account for this remarkable regenerative potential. Here, we report a key role for the male gonad, testosterone, and androgen receptor (AR) in CNS remyelination. After lysolecithin-induced demyelination of the male mouse ventral spinal cord white matter, the recruitment of glial fibrillary acidic protein-expressing astrocytes was compromised in the absence of testes and testosterone signaling via AR. Concomitantly, the differentiation of OPs into oligodendrocytes forming myelin basic protein (MBP)+and proteolipid protein-positive myelin was impaired. Instead, in the absence of astrocytes, axons were remyelinated by protein zero (P0)+and peripheral myelin protein 22-kDa (PMP22)+myelin, normally only produced by Schwann cells in the peripheral nervous system. Thus, testosterone favors astrocyte recruitment and spontaneous oligodendrocyte-mediated remyelination. This finding may have important implications for demyelinating diseases, psychiatric disorders, and cognitive aging. The testosterone dependency of CNS oligodendrocyte remyelination may have roots in the evolutionary history of the AR, because the receptor has evolved from an ancestral 3-ketosteroid receptor through gene duplication at the time when myelin appeared in jawed vertebrates.
authors.affiliation: U1195 INSERM, University Paris-Sud, University Paris-Saclay, Kremlin-Bicêtre 94276, France.|Department of Neurology and Stroke, Medical University of Lodz, Lodz 90-549, Poland.
authors.forename: Bartosz
authors.initials: B
authors.lastname: Bielecki
authors.affiliation: Mattern Foundation, Vaduz 9490, Liechtenstein.
authors.forename: Claudia
authors.initials: C
authors.lastname: Mattern
authors.affiliation: U1195 INSERM, University Paris-Sud, University Paris-Saclay, Kremlin-Bicêtre 94276, France.
authors.forename: Abdel M
authors.initials: AM
authors.lastname: Ghoumari
authors.affiliation: U1195 INSERM, University Paris-Sud, University Paris-Saclay, Kremlin-Bicêtre 94276, France.|Hussain Ebrahim Jamal Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
authors.forename: Sumaira
authors.initials: S
authors.lastname: Javaid
authors.affiliation: U1195 INSERM, University Paris-Sud, University Paris-Saclay, Kremlin-Bicêtre 94276, France.|Department of Neurology and Stroke, Medical University of Lodz, Lodz 90-549, Poland.
authors.forename: Kaja
authors.initials: K
authors.lastname: Smietanka
authors.affiliation: U1195 INSERM, University Paris-Sud, University Paris-Saclay, Kremlin-Bicêtre 94276, France.
authors.forename: Charly
authors.initials: C
authors.lastname: Abi Ghanem
authors.affiliation: U1130 INSERM, UMR 8246 CNRS, University Pierre and Marie Curie, Paris 75005, France.
authors.forename: Sakina
authors.initials: S
authors.lastname: Mhaouty-Kodja
authors.affiliation: UMR 7357 CNRS, University of Strasbourg, Strasbourg 67000, France.|Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond 23284, VA.
authors.forename: M Said
authors.initials: MS
authors.lastname: Ghandour
authors.affiliation: U1195 INSERM, University Paris-Sud, University Paris-Saclay, Kremlin-Bicêtre 94276, France; etienne.baulieu@inserm.fr michael.schumacher@inserm.fr.
authors.forename: Etienne-Emile
authors.initials: EE
authors.lastname: Baulieu
authors.affiliation: Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0AH, United Kingdom.|Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0AH, United Kingdom.
authors.forename: Robin J M
authors.initials: RJ
authors.lastname: Franklin
authors.affiliation: U1195 INSERM, University Paris-Sud, University Paris-Saclay, Kremlin-Bicêtre 94276, France; etienne.baulieu@inserm.fr michael.schumacher@inserm.fr.
authors.forename: Michael
authors.initials: M
authors.lastname: Schumacher
authors.affiliation: U1195 INSERM, University Paris-Sud, University Paris-Saclay, Kremlin-Bicêtre 94276, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Traiffort
mesh_terms: D000728:Androgens / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D002490:Central Nervous System / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009186:Myelin Sheath / Q000378:metabolism*; D009457:Neuroglia / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D011987:Receptors, Steroid / Q000378:metabolism; D000074586:Remyelination; D012583:Schwann Cells / Q000378:metabolism; D015398:Signal Transduction; D013737:Testis / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism
chemical_list: C000607144:AR protein, mouse; D000728:Androgens; D011944:Receptors, Androgen; D011987:Receptors, Steroid; D049452:Green Fluorescent Proteins; D013739:Testosterone
keywords: Schwann cells; androgen receptor; myelin; oligodendrocytes; testosterone