The role of the common neurotrophin receptor p75 (p75NTR) in neuronal survival and cell death remains controversial. On the one hand, p75NTR provides a positive modulatory influence on nerve growth factor (NGF) signaling through the high affinity neurotrophin receptor TrkA, and hence increases NGF survival signaling. However, p75NTR may also signal independently of TrkA, causing cell death or cell survival, depending on the cell type and stage of development. Here we demonstrate that TrkA is expressed in primary cultures of hippocampal neurons and is activated by NGF within 10 min of exposure. In primary hippocampal cultures neuroprotection by NGF against glutamate toxicity was mediated by NF-κB and accompanied by an increased expression of neuroprotective NF-κB target genes Bcl-2 and Bcl-xl. In mouse hippocampal cells lacking p75NTR (p75NTR-/-) activation of TrkA by NGF was not detectable. Moreover, neuroprotection by NGF against glutamate toxicity was abolished in p75NTR-/- neurons, and the expression of bcl-2 and bcl-xl was markedly reduced as compared to wildtype cells. NGF increased TrkA phosphorylation in hippocampal neurons and provided protection that required phosphoinositol-3-phosphate (PI3)-kinase activity and Akt phosphorylation, whereas the mitogen-activated protein kinases (MAPK), extracellular-regulated kinases (Erk) 1/2, were not involved. P75NTR signaling independent of TrkA, such as increased neutral sphingomyelinase (NSMase) activity causing enhanced levels of ceramide, were not detected after exposure of hippocampal neurons to NGF. Interestingly, inhibition of sphingosine-kinase blocked the neuroprotective effect of NGF, suggesting that sphingosine-1-phosphate was also involved in NGF-mediated survival in our cultured hippocampal neurons. Overall, our results indicate an essential role for p75NTR in supporting NGF-triggered TrkA signaling pathways mediating neuronal survival in hippocampal neurons.
|Number of pages||20|
|State||Published - Dec 16 2002|
Bibliographical noteFunding Information:
The authors thank Prof. Dr. Michael Sendtner, University of Würzburg, for providing breeding pairs of p75NTR−/− mice, and Prof. Dr. Thomas Herdegen and Dr. Stephan Brecht, University of Kiel, for their support in establishing p75NTR−/− mouse colonies. We are grateful to Dr. Alex Kuan at Yale University for providing breeding pairs of κB-luciferase reporter mice. We thank Prof. Dr. Louis Reichardt, University of California, San Francisco, USA for the generous gift of TrkA-antibody, and Prof. Dr. Takeshi Ogita, Sankyo, Tokyo, Japan, for the generous gift of scyphostatin. Excellent technical assistance by Ms. Sandy Little, Ms. Sandra Engel and Ms. Michaela Stumpf is gratefully acknowledged. The present work was supported by DFG grants to C.C. and J.K., and by NIH grants to M.P.M.
- Shingosine kinase
ASJC Scopus subject areas
- Neuroscience (all)