Developmental axon pruning mediated by BDNF-p75NTR-dependent axon degeneration.
The mechanisms that regulate the pruning of mammalian axons are just now being elucidated. Here, we describe a mechanism by which, during developmental sympathetic axon competition, winning axons secrete brain-derived neurotrophic factor (BDNF) in an activity-dependent fashion, which binds to the p75 neurotrophin receptor (p75NTR) on losing axons to cause their degeneration and, ultimately, axon pruning. Specifically, we found that pruning of rat and mouse sympathetic axons that project to the eye requires both activity-dependent BDNF and p75NTR. p75NTR and BDNF are also essential for activity-dependent axon pruning in culture, where they mediate pruning by directly causing axon degeneration. p75NTR, which is enriched in losing axons, causes axonal degeneration by suppressing TrkA-mediated signaling that is essential for axonal maintenance. These data provide a mechanism that explains how active axons can eliminate less-active, competing axons during developmental pruning by directly promoting p75NTR-mediated axonal degeneration.
Singh
Karun K
KK
Developmental and Stem Cell Biology, Hospital for Sick Children, 555 University Avenue, Toronto, Canada M5G 1X8.
Park
Katya J
KJ
Hong
Elizabeth J
EJ
Kramer
Bianca M
BM
Greenberg
Michael E
ME
Kaplan
David R
DR
Miller
Freda D
FD
D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000187:drug effects / Q000502:physiology*; D019771:Axotomy / Q000379:methods; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology / Q000502:physiology*; D002478:Cells, Cultured; D002772:Cholera Toxin / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology*; D020932:Nerve Growth Factor / Q000494:pharmacology; D009474:Neurons / Q000166:cytology; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020800:Receptor, Nerve Growth Factor / Q000172:deficiency / Q000502:physiology*; D013266:Stilbamidines / Q000378:metabolism; D017783:Superior Cervical Ganglion / Q000166:cytology / Q000254:growth & development; D014795:Visual Pathways / Q000254:growth & development / Q000378:metabolism
C049774:2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt; D019208:Brain-Derived Neurotrophic Factor; D004791:Enzyme Inhibitors; D020800:Receptor, Nerve Growth Factor; D013266:Stilbamidines; D049452:Green Fluorescent Proteins; D011189:Potassium Chloride; D002772:Cholera Toxin; D020932:Nerve Growth Factor