Neuropilin-1 is a direct target of the transcription factor E2F1 during cerebral ischemia-induced neuronal death in vivo

  1. Get@NRC: Neuropilin-1 is a direct target of the transcription factor E2F1 during cerebral ischemia-induced neuronal death in vivo (Opens in a new window)
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Journal titleMol.Cell Biol.
Pages16961705; # of pages: 10
SubjectAdenoviridae; analysis; Animals; assay; binding; BINDING-SITE; Brain; Brain Death; Brain Ischemia; Canada; Cells,Cultured; Cerebellum; Chromatin Immunoprecipitation; cytology; DNA; E2F1 Transcription Factor; Electrophoretic Mobility Shift Assay; etiology; EXPRESSION; GENE; Gene Expression; Genes; Genes,Reporter; genetics; Immunoprecipitation; INHIBITOR; Ischemia; LED; Luciferases; metabolism; Mice; Mice,Inbred C57BL; Mice,Mutant Strains; MODEL; Models,Biological; Neuroglia; Neurons; Neuropilin-1; NUCLEAR; Oligonucleotide Array Sequence Analysis; pathology; peptide; Promoter Regions (Genetics); receptor; Reverse Transcriptase Polymerase Chain Reaction; Role; selective; SEQUENCE; SITE; TARGET
AbstractThe nuclear transcription factor E2F1 plays an important role in modulating neuronal death in response to excitotoxicity and cerebral ischemia. Here, by comparing gene expression in brain cortices from E2F1(+/+) and E2F1(-/-) mice using a custom high-density DNA microarray, we identified a group of putative E2F1 target genes that might be responsible for ischemia-induced E2F1-dependent neuronal death. Neuropilin 1 (NRP-1), a receptor for semaphorin 3A-mediated axon growth cone collapse and retraction, was confirmed to be a direct target of E2F1 based on (i) the fact that the NRP-1 promoter sequence contains an E2F1 binding site, (ii) reactivation of NRP-1 expression in E2F1(-/-) neurons when the E2F1 gene was replaced, (iii) activation of the NRP-1 promoter by E2F1 in a luciferase reporter assay, (iv) electrophoretic mobility gel shift analysis confirmation of the presence of an E2F binding sequence in the NRP-1 promoter, and (v) the fact that a chromatin immunoprecipitation assay showed that E2F1 binds directly to the endogenous NRP-1 promoter. Interestingly, the temporal induction in cerebral ischemia-induced E2F1 binding to the NRP-1 promoter correlated with the temporal-induction profile of NRP-1 mRNA, confirming that E2F1 positively regulates NRP-1 during cerebral ischemia. Functional analysis also showed that NRP-1 receptor expression was extremely low in E2F1(-/-) neurons, which led to the diminished response to semaphorin 3A-induced axonal shortening and neuronal death. An NRP-1 selective peptide inhibitor provided neuroprotection against oxygen-glucose deprivation. Taken together, these findings support a model in which E2F1 targets NRP-1 to modulate axonal damage and neuronal death in response to cerebral ischemia
Publication date
AffiliationNRC Institute for Biological Sciences; National Research Council Canada
Peer reviewedNo
NRC numberJIANG2007A
NPARC number9375964
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Record identifierc694f0d3-21e0-4942-8a9a-a50d9119efc6
Record created2009-07-10
Record modified2016-05-09
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