p75(NTR) mediates ephrin-A reverse signaling required for axon repulsion and mapping.
Reverse signaling by ephrin-As upon binding EphAs controls axon guidance and mapping. Ephrin-As are GPI-anchored to the membrane, requiring that they complex with transmembrane proteins that transduce their signals. We show that the p75 neurotrophin receptor (NTR) serves this role in retinal axons. p75(NTR) and ephrin-A colocalize within caveolae along retinal axons and form a complex required for Fyn phosphorylation upon binding EphAs, activating a signaling pathway leading to cytoskeletal changes. In vitro, retinal axon repulsion to EphAs by ephrin-A reverse signaling requires p75(NTR), but repulsion to ephrin-As by EphA forward signaling does not. Constitutive and retina-specific p75(NTR) knockout mice have aberrant anterior shifts in retinal axon terminations in superior colliculus, consistent with diminished repellent activity mediated by graded ephrin-A reverse signaling induced by graded collicular EphAs. We conclude that p75(NTR) is a signaling partner for ephrin-As and the ephrin-A- p75(NTR) complex reverse signals to mediate axon repulsion required for guidance and mapping.
Lim
Yoo-Shick
YS
Molecular Neurobiology Laboratory, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
McLaughlin
Todd
T
Sung
Tsung-Chang
TC
Santiago
Alicia
A
Lee
Kuo-Fen
KF
O'Leary
Dennis D M
DD
D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000502:physiology*; D001931:Brain Mapping; D002461:Cell Line, Transformed; D036342:Ephrins / Q000378:metabolism*; D019922:GAP-43 Protein / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism; D051381:Rats; D017475:Receptors, Nerve Growth Factor; D012160:Retina / Q000166:cytology; D012165:Retinal Ganglion Cells / Q000166:cytology* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D014795:Visual Pathways / Q000502:physiology
D000596:Amino Acids; D036342:Ephrins; D019922:GAP-43 Protein; C484065:NGFR protein, human; D009419:Nerve Tissue Proteins; D017475:Receptors, Nerve Growth Factor; C098463:dolaisoleucine; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn
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