NGF regulates the expression of axonal LINGO-1 to inhibit oligodendrocyte differentiation and myelination.
Neurons and glia share a mutual dependence in establishing a functional relationship, and none is more evident than the process by which axons control myelination. Here, we identify LRR and Ig domain-containing, Nogo receptor-interacting protein (LINGO-1) as a potent axonal inhibitor of oligodendrocyte differentiation and myelination that is regulated by nerve growth factor and its cognate receptor TrkA in a dose-dependent manner. Whereas LINGO-1 expressed by oligodendrocyte progenitor cells was previously identified as an inhibitor of differentiation, we demonstrate that axonal expression of LINGO-1 inhibits differentiation with equal potency. Disruption of LINGO-1 on either cell type is sufficient to overcome the inhibitory action and promote differentiation and myelination, independent of axon diameter. Furthermore, these results were recapitulated in transgenic mice overexpressing the full length LINGO-1 under the neuronal promoter synapsin. Myelination was greatly inhibited in the presence of enforced axonal LINGO-1. The implications of these results relate specifically to the development of potential therapeutics targeting extrinsic growth factors that may regulate the axonal expression of modulators of oligodendrocyte development.
Lee
Xinhua
X
Department of Discovery Biology, Biogen Idec, Cambridge, Massachusetts 02142, USA.
Yang
Zhongshu
Z
Shao
Zhaohui
Z
Rosenberg
Sheila S
SS
Levesque
Melissa
M
Pepinsky
R Blake
RB
Qiu
Mengsheng
M
Miller
Robert H
RH
Chan
Jonah R
JR
Mi
Sha
S
D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D009413:Nerve Fibers, Myelinated / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D020932:Nerve Growth Factor / Q000008:administration & dosage*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009836:Oligodendroglia / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D020917:Receptor, trkA / Q000378:metabolism
C482293:LINGO1 protein, human; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D020932:Nerve Growth Factor; D020917:Receptor, trkA