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The death receptor antagonist FAIM promotes neurite outgrowth by a mechanism that depends on ERK and NF-kapp B signaling.

Sole C, Dolcet X, Segura MF, Gutierrez H, Diaz-Meco MT, Gozzelino R, Sanchis D, Bayascas JR, Gallego C, Moscat J, Davies AM, Comella JX - J. Cell Biol. (2004)

Bottom Line: Whereas FAIM overexpression greatly enhanced neurite outgrowth from PC12 cells and sympathetic neurons grown with nerve growth factor (NGF), reduction of endogenous FAIM levels by RNAi decreased neurite outgrowth in these cells.The effect of FAIM on neurite outgrowth was also blocked by inhibition of the Ras-ERK pathway.These results reveal a new function of FAIM in promoting neurite outgrowth by a mechanism involving activation of the Ras-ERK pathway and NF-kappa B.

View Article: PubMed Central - PubMed

Affiliation: Group Cell Signalling and Apoptosis, Department of Basic Medical Sciences, Universitat de Lleida, 25008 Lleida, Spain.

ABSTRACT
Fas apoptosis inhibitory molecule (FAIM) is a protein identified as an antagonist of Fas-induced cell death. We show that FAIM overexpression fails to rescue neurons from trophic factor deprivation, but exerts a marked neurite growth-promoting action in different neuronal systems. Whereas FAIM overexpression greatly enhanced neurite outgrowth from PC12 cells and sympathetic neurons grown with nerve growth factor (NGF), reduction of endogenous FAIM levels by RNAi decreased neurite outgrowth in these cells. FAIM overexpression promoted NF-kappa B activation, and blocking this activation by using a super-repressor I kappa B alpha or by carrying out experiments using cortical neurons from mice that lack the p65 NF-kappa B subunit prevented FAIM-induced neurite outgrowth. The effect of FAIM on neurite outgrowth was also blocked by inhibition of the Ras-ERK pathway. Finally, we show that FAIM interacts with both Trk and p75 neurotrophin receptor NGF receptors in a ligand-dependent manner. These results reveal a new function of FAIM in promoting neurite outgrowth by a mechanism involving activation of the Ras-ERK pathway and NF-kappa B.

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FAIM increases NGF-induced neurite outgrowth in mouse SCG neurons. Ballistic transfections of cultured neurons with an eYFP expression plasmid together with the Neo control vector or FAIM-S plasmids. After 24-h incubation with NGF (10 ng/ml), eYFP-labeled SCG were visualized and digitally acquired. (A) Representative drawings of the neurons corresponding to the 25, 50, 75, and 100 percentiles of the neurite length are shown. (B) Representative micrographs showing the FAIM-increased neuritic outgrowth. Bars, 50 μm. (C) Quantification of neurite length (top) and branching points (bottom). Significant differences in neurite length between Neo and FAIM are indicated (*, P < 0.05 and **, P < 0.001, respectively; t test).
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fig3: FAIM increases NGF-induced neurite outgrowth in mouse SCG neurons. Ballistic transfections of cultured neurons with an eYFP expression plasmid together with the Neo control vector or FAIM-S plasmids. After 24-h incubation with NGF (10 ng/ml), eYFP-labeled SCG were visualized and digitally acquired. (A) Representative drawings of the neurons corresponding to the 25, 50, 75, and 100 percentiles of the neurite length are shown. (B) Representative micrographs showing the FAIM-increased neuritic outgrowth. Bars, 50 μm. (C) Quantification of neurite length (top) and branching points (bottom). Significant differences in neurite length between Neo and FAIM are indicated (*, P < 0.05 and **, P < 0.001, respectively; t test).

Mentions: To ascertain whether or not FAIM has a similar effect on NGF-induced neurite outgrowth in NGF-dependent primary neurons, we repeated these experiments using primary cultures of SCG neurons. Postnatal day (P1) mouse SCG neurons were plated and transiently cotransfected using gold carriers coated with both an eYFP expression plasmid (to visualize the transfected neurons) plus plasmids expressing FLAG-FAIM or the corresponding empty vector. The neurons were grown for 24 h in presence of NGF before the neuron arbors were captured in the confocal microscope and drawn using the confocal software. Fig. 3 (A and B) illustrates drawings and pictures of representative SCG neurons showing an increase in the neuritic arbor in FAIM-transfected neurons compared with the cultures transfected with the empty vector. Quantification of neurite length and number of branching points shows that FAIM induced a significant increase in these parameters (Fig. 3 C). These results indicate that FAIM is capable of regulating neurite length in sympathetic neurons.


The death receptor antagonist FAIM promotes neurite outgrowth by a mechanism that depends on ERK and NF-kapp B signaling.

Sole C, Dolcet X, Segura MF, Gutierrez H, Diaz-Meco MT, Gozzelino R, Sanchis D, Bayascas JR, Gallego C, Moscat J, Davies AM, Comella JX - J. Cell Biol. (2004)

FAIM increases NGF-induced neurite outgrowth in mouse SCG neurons. Ballistic transfections of cultured neurons with an eYFP expression plasmid together with the Neo control vector or FAIM-S plasmids. After 24-h incubation with NGF (10 ng/ml), eYFP-labeled SCG were visualized and digitally acquired. (A) Representative drawings of the neurons corresponding to the 25, 50, 75, and 100 percentiles of the neurite length are shown. (B) Representative micrographs showing the FAIM-increased neuritic outgrowth. Bars, 50 μm. (C) Quantification of neurite length (top) and branching points (bottom). Significant differences in neurite length between Neo and FAIM are indicated (*, P < 0.05 and **, P < 0.001, respectively; t test).
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Related In: Results  -  Collection

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fig3: FAIM increases NGF-induced neurite outgrowth in mouse SCG neurons. Ballistic transfections of cultured neurons with an eYFP expression plasmid together with the Neo control vector or FAIM-S plasmids. After 24-h incubation with NGF (10 ng/ml), eYFP-labeled SCG were visualized and digitally acquired. (A) Representative drawings of the neurons corresponding to the 25, 50, 75, and 100 percentiles of the neurite length are shown. (B) Representative micrographs showing the FAIM-increased neuritic outgrowth. Bars, 50 μm. (C) Quantification of neurite length (top) and branching points (bottom). Significant differences in neurite length between Neo and FAIM are indicated (*, P < 0.05 and **, P < 0.001, respectively; t test).
Mentions: To ascertain whether or not FAIM has a similar effect on NGF-induced neurite outgrowth in NGF-dependent primary neurons, we repeated these experiments using primary cultures of SCG neurons. Postnatal day (P1) mouse SCG neurons were plated and transiently cotransfected using gold carriers coated with both an eYFP expression plasmid (to visualize the transfected neurons) plus plasmids expressing FLAG-FAIM or the corresponding empty vector. The neurons were grown for 24 h in presence of NGF before the neuron arbors were captured in the confocal microscope and drawn using the confocal software. Fig. 3 (A and B) illustrates drawings and pictures of representative SCG neurons showing an increase in the neuritic arbor in FAIM-transfected neurons compared with the cultures transfected with the empty vector. Quantification of neurite length and number of branching points shows that FAIM induced a significant increase in these parameters (Fig. 3 C). These results indicate that FAIM is capable of regulating neurite length in sympathetic neurons.

Bottom Line: Whereas FAIM overexpression greatly enhanced neurite outgrowth from PC12 cells and sympathetic neurons grown with nerve growth factor (NGF), reduction of endogenous FAIM levels by RNAi decreased neurite outgrowth in these cells.The effect of FAIM on neurite outgrowth was also blocked by inhibition of the Ras-ERK pathway.These results reveal a new function of FAIM in promoting neurite outgrowth by a mechanism involving activation of the Ras-ERK pathway and NF-kappa B.

View Article: PubMed Central - PubMed

Affiliation: Group Cell Signalling and Apoptosis, Department of Basic Medical Sciences, Universitat de Lleida, 25008 Lleida, Spain.

ABSTRACT
Fas apoptosis inhibitory molecule (FAIM) is a protein identified as an antagonist of Fas-induced cell death. We show that FAIM overexpression fails to rescue neurons from trophic factor deprivation, but exerts a marked neurite growth-promoting action in different neuronal systems. Whereas FAIM overexpression greatly enhanced neurite outgrowth from PC12 cells and sympathetic neurons grown with nerve growth factor (NGF), reduction of endogenous FAIM levels by RNAi decreased neurite outgrowth in these cells. FAIM overexpression promoted NF-kappa B activation, and blocking this activation by using a super-repressor I kappa B alpha or by carrying out experiments using cortical neurons from mice that lack the p65 NF-kappa B subunit prevented FAIM-induced neurite outgrowth. The effect of FAIM on neurite outgrowth was also blocked by inhibition of the Ras-ERK pathway. Finally, we show that FAIM interacts with both Trk and p75 neurotrophin receptor NGF receptors in a ligand-dependent manner. These results reveal a new function of FAIM in promoting neurite outgrowth by a mechanism involving activation of the Ras-ERK pathway and NF-kappa B.

Show MeSH
Related in: MedlinePlus