Neuropilin 1 directly interacts with Fer kinase to mediate semaphorin 3A-induced death of cortical neurons.
Neuropilins (NRPs) are receptors for the major chemorepulsive axonal guidance cue semaphorins (Sema). The interaction of Sema3A/NRP1 during development leads to the collapse of growth cones. Here we show that Sema3A also induces death of cultured cortical neurons through NRP1. A specific NRP1 inhibitory peptide ameliorated Sema3A-evoked cortical axonal retraction and neuronal death. Moreover, Sema3A was also involved in cerebral ischemia-induced neuronal death. Expression levels of Sema3A and NRP1, but not NRP2, were significantly increased early during brain reperfusion following transient focal cerebral ischemia. NRP1 inhibitory peptide delivered to the ischemic brain was potently neuroprotective and prevented the loss of motor functions in mice. The integrity of the injected NRP1 inhibitory peptide into the brain remained unchanged, and the intact peptide permeated the ischemic hemisphere of the brain as determined using MALDI-MS-based imaging. Mechanistically, NRP1-mediated axonal collapse and neuronal death is through direct and selective interaction with the cytoplasmic tyrosine kinase Fer. Fer RNA interference effectively attenuated Sema3A-induced neurite retraction and neuronal death in cortical neurons. More importantly, down-regulation of Fer expression using Fer-specific RNA interference attenuated cerebral ischemia-induced brain damage. Together, these studies revealed a previously unknown function of NRP1 in signaling Sema3A-evoked neuronal death through Fer in cortical neurons.
Jiang
Susan X
SX
Experimental NeuroTherapeutics Laboratory, Ottawa, Ontario K1A 0R6, Canada.
Whitehead
Shawn
S
Experimental NeuroTherapeutics Laboratory, Ottawa, Ontario K1A 0R6, Canada.
Aylsworth
Amy
A
Experimental NeuroTherapeutics Laboratory, Ottawa, Ontario K1A 0R6, Canada; Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ontario K1H 8M5, Canada.
Slinn
Jacqueline
J
Experimental NeuroTherapeutics Laboratory, Ottawa, Ontario K1A 0R6, Canada.
Zurakowski
Bogdan
B
Experimental NeuroTherapeutics Laboratory, Ottawa, Ontario K1A 0R6, Canada.
Chan
Kenneth
K
Mass Spectrometry Glycoanalysis Laboratory, National Research Council (NRC) Institute for Biological Sciences, NRC Canada, Ottawa, Ontario K1A 0R6, Canada.
Li
Jianjun
J
Mass Spectrometry Glycoanalysis Laboratory, National Research Council (NRC) Institute for Biological Sciences, NRC Canada, Ottawa, Ontario K1A 0R6, Canada.
Hou
Sheng T
ST
Experimental NeuroTherapeutics Laboratory, Ottawa, Ontario K1A 0R6, Canada; Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ontario K1H 8M5, Canada. Electronic address: sheng.hou@nrc-cnrc.gc.ca.
D000818:Animals; D001921:Brain / Q000378:metabolism; D002545:Brain Ischemia / Q000473:pathology; D016923:Cell Death; D015971:Gene Expression Regulation, Enzymologic; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism; D039942:Neuropilin-1 / Q000737:chemistry / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D034622:RNA Interference; D040121:Semaphorin-3A / Q000737:chemistry*; D015398:Signal Transduction
D010455:Peptides; D040121:Semaphorin-3A; C052602:proto-oncogene protein c-fes-fps; D039942:Neuropilin-1; D011505:Protein-Tyrosine Kinases