title: Neurite outgrowth inhibitor Nogo-A establishes spatial segregation and extent of oligodendrocyte myelination.
abstract: A requisite component of nervous system development is the achievement of cellular recognition and spatial segregation through competition-based refinement mechanisms. Competition for available axon space by myelinating oligodendrocytes ensures that all relevant CNS axons are myelinated properly. To ascertain the nature of this competition, we generated a transgenic mouse with sparsely labeled oligodendrocytes and establish that individual oligodendrocytes occupying similar axon tracts can greatly vary the number and lengths of their myelin internodes. Here we show that intercellular interactions between competing oligodendroglia influence the number and length of myelin internodes, referred to as myelinogenic potential, and identify the amino-terminal region of Nogo-A, expressed by oligodendroglia, as necessary and sufficient to inhibit this process. Exuberant and expansive myelination/remyelination is detected in the absence of Nogo during development and after demyelination, suggesting that spatial segregation and myelin extent is limited by microenvironmental inhibition. We demonstrate a unique physiological role for Nogo-A in the precise myelination of the developing CNS. Maximizing the myelinogenic potential of oligodendrocytes may offer an effective strategy for repair in future therapies for demyelination.
authors.affiliation: Department of Neurology and Program in Neuroscience, University of California, San Francisco, CA 94143, USA.
authors.forename: S Y Christin
authors.initials: SY
authors.lastname: Chong
authors.forename: Sheila S
authors.initials: SS
authors.lastname: Rosenberg
authors.forename: Stephen P J
authors.initials: SP
authors.lastname: Fancy
authors.forename: Chao
authors.initials: C
authors.lastname: Zhao
authors.forename: Yun-An A
authors.initials: YA
authors.lastname: Shen
authors.forename: Angela T
authors.initials: AT
authors.lastname: Hahn
authors.forename: Aaron W
authors.initials: AW
authors.lastname: McGee
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Xu
authors.forename: Binhai
authors.initials: B
authors.lastname: Zheng
authors.forename: Li I
authors.initials: LI
authors.lastname: Zhang
authors.forename: David H
authors.initials: DH
authors.lastname: Rowitch
authors.forename: Robin J M
authors.initials: RJ
authors.lastname: Franklin
authors.forename: Q Richard
authors.initials: QR
authors.lastname: Lu
authors.forename: Jonah R
authors.initials: JR
authors.lastname: Chan
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002490:Central Nervous System / Q000166:cytology / Q000473:pathology*; D003711:Demyelinating Diseases / Q000503:physiopathology*; D055785:Gene Knockdown Techniques; D006652:Histological Techniques; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008863:Microspheres; D009185:Myelin Proteins / Q000235:genetics / Q000378:metabolism*; D009186:Myelin Sheath / Q000502:physiology*; D000070798:Nogo Proteins; D009836:Oligodendroglia / Q000378:metabolism / Q000502:physiology* / Q000648:ultrastructure; D011137:Polystyrenes; D034741:RNA, Small Interfering / Q000235:genetics; D014461:Ultracentrifugation
chemical_list: D009185:Myelin Proteins; D000070798:Nogo Proteins; D011137:Polystyrenes; D034741:RNA, Small Interfering; C000603201:Rtn4 protein, mouse