Cellular form of prion protein inhibits Reelin-mediated shedding of Caspr from the neuronal cell surface to potentiate Caspr-mediated inhibition of neurite outgrowth.
Extension of axonal and dendritic processes in the CNS is tightly regulated by outgrowth-promoting and -inhibitory cues to assure precision of synaptic connections. We identify a novel role for contactin-associated protein (Caspr) as an inhibitory cue that reduces neurite outgrowth from CNS neurons. We show that proteolysis of Caspr at the cell surface is regulated by the cellular form of prion protein (PrP), which directly binds to Caspr. PrP inhibits Reelin-mediated shedding of Caspr from the cell surface, thereby increasing surface levels of Caspr and potentiating the inhibitory effect of Caspr on neurite outgrowth. PrP deficiency results in reduced levels of Caspr at the cell surface, enhanced neurite outgrowth in vitro, and more efficient regeneration of axons in vivo following spinal cord injury. Thus, we reveal a previously unrecognized role for Caspr and PrP in inhibitory modulation of neurite outgrowth in CNS neurons, which is counterbalanced by the proteolytic activity of Reelin.
Devanathan
Vasudharani
V
Zentrum für Molekulare Neurobiologie, Universität Hamburg, Hamburg, Germany.
Jakovcevski
Igor
I
Santuccione
Antonella
A
Li
Shen
S
Lee
Hyun Joon
HJ
Peles
Elior
E
Leshchyns'ka
Iryna
I
Sytnyk
Vladimir
V
Schachner
Melitta
M
D000818:Animals; D019921:Biotinylation / Q000379:methods; D001921:Brain / Q000166:cytology; D016466:CHO Cells; D002395:Catecholamines / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal / Q000172:deficiency / Q000378:metabolism*; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D016326:Extracellular Matrix Proteins / Q000172:deficiency / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D020439:Growth Cones / Q000187:drug effects / Q000502:physiology; D047468:Immunoprecipitation / Q000379:methods; D008124:Locomotion / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000378:metabolism*; D016501:Neurites / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000166:cytology* / Q000648:ultrastructure; D011328:Prions / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D020127:Recovery of Function / Q000235:genetics; D000091042:Reelin Protein; D012694:Serine / Q000378:metabolism; D012697:Serine Endopeptidases / Q000172:deficiency / Q000378:metabolism*; D013116:Spinal Cord / Q000166:cytology; D013119:Spinal Cord Injuries / Q000473:pathology / Q000503:physiopathology; D013347:Subcellular Fractions / Q000378:metabolism; D013997:Time Factors; D014162:Transfection / Q000379:methods
D002395:Catecholamines; D015815:Cell Adhesion Molecules; D015816:Cell Adhesion Molecules, Neuronal; C490649:Chl1 protein, mouse; C491322:Cntnap1 protein, mouse; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D011328:Prions; D000091042:Reelin Protein; D012694:Serine; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases