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      Ceramide Signaling Downstream of the p75 Neurotrophin Receptor Mediates the Effects of Nerve Growth Factor on Outgrowth of Cultured Hippocampal Neurons

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          Abstract

          The p75 neurotrophin receptor (p75NTR) binds all known neurotrophins and has been suggested to either function as a coreceptor for the trk receptor tyrosine kinases or be involved in independent signaling leading to cell death. We have analyzed the effects of nerve growth factor (NGF) on the growth of cultured hippocampal pyramidal neurons and examined the possibility that the effects of NGF are mediated via generation of ceramide produced by neutral sphingomyelinase (N-SMase). During the initial hour of culture, the only detectable NGF receptor is p75NTR, which by comparative Western blot is expressed at 50- to 100-fold lower levels than on PC12 cells. At this early stage of culture, NGF accelerates neurite formation and outgrowth and induces ceramide formation in a dose-dependent manner. An NGF mutant that is deficient in p75NTR binding has no effect on neuronal morphology or ceramide formation. Furthermore, two anti-p75NTR antibodies (REX and 9651), which are known to compete with NGF for binding to p75NTR, mimic the effects of NGF, whereas a monoclonal antibody (MC192) targeted against a different epitope does not. Finally, scyphostatin, a specific N-SMase inhibitor, blocks the effects of NGF. We propose that a neurotrophin–p75NTR–ceramide signaling pathway influences outgrowth of hippocampal neurons. This signaling role of p75NTR may be distinct from other signaling pathways that lead to apoptosis.

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          Author and article information

          Journal
          J Neurosci
          J. Neurosci
          jneuro
          jneurosci
          J. Neurosci
          The Journal of Neuroscience
          Society for Neuroscience
          0270-6474
          1529-2401
          1 October 1999
          : 19
          : 19
          : 8199-8206
          Affiliations
          [ 1 ]Department of Biological Chemistry,
          [ 2 ]Molecular Neurobiology Group, Weizmann Institute of Science, Rehovot 76100, Israel
          Article
          PMC6783007 PMC6783007 6783007 3438
          10.1523/JNEUROSCI.19-19-08199.1999
          6783007
          10493721
          a26ddc80-d31c-483f-9d88-737b87da9384
          Copyright © 1999 Society for Neuroscience
          History
          : 14 April 1999
          : 4 June 1999
          : 12 July 1999
          Categories
          Article
          Custom metadata
          5.00

          p75NTR,NGF,neurotrophins,ceramide,sphingomyelin,neurons,axons
          p75NTR, NGF, neurotrophins, ceramide, sphingomyelin, neurons, axons

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