title: Metallothionein-I/II Promotes Axonal Regeneration in the Central Nervous System.
abstract: The adult CNS does not spontaneously regenerate after injury, due in large part to myelin-associated inhibitors such as myelin-associated glycoprotein (MAG), Nogo-A, and oligodendrocyte-myelin glycoprotein. All three inhibitors can interact with either the Nogo receptor complex or paired immunoglobulin-like receptor B. A conditioning lesion of the sciatic nerve allows the central processes of dorsal root ganglion (DRG) neurons to spontaneously regenerate in vivo after a dorsal column lesion. After a conditioning lesion, DRG neurons are no longer inhibited by myelin, and this effect is cyclic AMP (cAMP)- and transcription-dependent. Using a microarray analysis, we identified several genes that are up-regulated both in adult DRGs after a conditioning lesion and in DRG neurons treated with cAMP analogues. One gene that was up-regulated under both conditions is metallothionein (MT)-I. We show here that treatment with two closely related isoforms of MT (MT-I/II) can overcome the inhibitory effects of both myelin and MAG for cortical, hippocampal, and DRG neurons. Intrathecal delivery of MT-I/II to adult DRGs also promotes neurite outgrowth in the presence of MAG. Adult DRGs from MT-I/II-deficient mice extend significantly shorter processes on MAG compared with wild-type DRG neurons, and regeneration of dorsal column axons does not occur after a conditioning lesion in MT-I/II-deficient mice. Furthermore, a single intravitreal injection of MT-I/II after optic nerve crush promotes axonal regeneration. Mechanistically, MT-I/II ability to overcome MAG-mediated inhibition is transcription-dependent, and MT-I/II can block the proteolytic activity of α-secretase and the activation of PKC and Rho in response to soluble MAG.
authors.affiliation: From the Department of Biological Sciences, Hunter College, City University of New York, New York 10065 and mustafa.siddiq@mssm.edu.
authors.forename: Mustafa M
authors.initials: MM
authors.lastname: Siddiq
authors.affiliation: From the Department of Biological Sciences, Hunter College, City University of New York, New York 10065 and.
authors.forename: Sari S
authors.initials: SS
authors.lastname: Hannila
authors.affiliation: the W. M. Keck Center for Collaborative Neuroscience and Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854.
authors.forename: Jason B
authors.initials: JB
authors.lastname: Carmel
authors.affiliation: From the Department of Biological Sciences, Hunter College, City University of New York, New York 10065 and.
authors.forename: John B
authors.initials: JB
authors.lastname: Bryson
authors.affiliation: From the Department of Biological Sciences, Hunter College, City University of New York, New York 10065 and.
authors.forename: Jianwei
authors.initials: J
authors.lastname: Hou
authors.affiliation: From the Department of Biological Sciences, Hunter College, City University of New York, New York 10065 and.
authors.forename: Elena
authors.initials: E
authors.lastname: Nikulina
authors.affiliation: From the Department of Biological Sciences, Hunter College, City University of New York, New York 10065 and.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Willis
authors.affiliation: From the Department of Biological Sciences, Hunter College, City University of New York, New York 10065 and.
authors.forename: Wilfredo
authors.initials: W
authors.lastname: Mellado
authors.affiliation: From the Department of Biological Sciences, Hunter College, City University of New York, New York 10065 and.
authors.forename: Erica L
authors.initials: EL
authors.lastname: Richman
authors.affiliation: From the Department of Biological Sciences, Hunter College, City University of New York, New York 10065 and.
authors.forename: Melissa
authors.initials: M
authors.lastname: Hilaire
authors.affiliation: the W. M. Keck Center for Collaborative Neuroscience and Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854.
authors.forename: Ronald P
authors.initials: RP
authors.lastname: Hart
authors.affiliation: From the Department of Biological Sciences, Hunter College, City University of New York, New York 10065 and.
authors.forename: Marie T
authors.initials: MT
authors.lastname: Filbin
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism*; D002490:Central Nervous System / Q000293:injuries / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D008297:Male; D008668:Metallothionein / Q000235:genetics / Q000378:metabolism*; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000378:metabolism; D018992:Myelin-Associated Glycoprotein / Q000378:metabolism; D009416:Nerve Regeneration; D051381:Rats; D020318:Rats, Long-Evans
chemical_list: C491055:Mt2A protein, rat; D018992:Myelin-Associated Glycoprotein; D008668:Metallothionein
keywords: axonal regeneration; central nervous system (CNS); cyclic AMP (cAMP); metallothionein; myelin; neurite outgrowth; regeneration