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TrkA mediates developmental sympathetic neuron survival in vivo by silencing an ongoing p75NTR-mediated death signal.

Majdan M, Walsh GS, Aloyz R, Miller FD - J. Cell Biol. (2001)

Bottom Line: A key question is whether p75NTR promotes apoptosis by directly inhibiting or modulating TrkA activity, or by stimulating cell death independently of TrkA.Here we provide evidence for the latter model.These data therefore support a model where developing sympathetic neurons are "destined to die" by an ongoing p75NTR-mediated apoptotic signal, and one of the major ways that TrkA promotes neuronal survival is by silencing this ongoing death signal.

View Article: PubMed Central - PubMed

Affiliation: Center for Neuronal Survival, Montreal Neurological Institute, McGill University, Montreal, Canada H3A 2B4.

ABSTRACT
Developmental sympathetic neuron death is determined by functional interactions between the TrkA/NGF receptor and the p75 neurotrophin receptor (p75NTR). A key question is whether p75NTR promotes apoptosis by directly inhibiting or modulating TrkA activity, or by stimulating cell death independently of TrkA. Here we provide evidence for the latter model. Specifically, experiments presented here demonstrate that the presence or absence of p75NTR does not alter Trk activity or NGF- and NT-3-mediated downstream survival signaling in primary neurons. Crosses of p75NTR-/- and TrkA-/- mice indicate that the coincident absence of p75NTR substantially rescues TrkA-/- sympathetic neurons from developmental death in vivo. Thus, p75NTR induces death regardless of the presence or absence of TrkA expression. These data therefore support a model where developing sympathetic neurons are "destined to die" by an ongoing p75NTR-mediated apoptotic signal, and one of the major ways that TrkA promotes neuronal survival is by silencing this ongoing death signal.

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The increase in sympathetic neuron number in the neonatal p75NTR−/− SCG is due to reduced apoptosis, not increased proliferation. (A) Fluorescence photomicrographs of TUNEL analysis of representative sections through the P2 SCG of p75NTR+/+ and p75NTR−/− animals. (B) Quantitation of TUNEL analysis similar to that seen in A. Numbers represent the total mean number of apoptotic nuclei in the SCG of p75NTR+/+ (control) versus p75NTR−/− (p75−/−) animals. (**P < 0.0005, n = 3). (C) Percentage of BrdU-positive cells with neuronal morphology in the p75NTR+/+ (control) versus p75NTR−/− (p75−/−) SCG at P3 and P4 (P = 0.4, n = 3 for each group). In both cases, error bars represent the standard error of the mean.
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fig1: The increase in sympathetic neuron number in the neonatal p75NTR−/− SCG is due to reduced apoptosis, not increased proliferation. (A) Fluorescence photomicrographs of TUNEL analysis of representative sections through the P2 SCG of p75NTR+/+ and p75NTR−/− animals. (B) Quantitation of TUNEL analysis similar to that seen in A. Numbers represent the total mean number of apoptotic nuclei in the SCG of p75NTR+/+ (control) versus p75NTR−/− (p75−/−) animals. (**P < 0.0005, n = 3). (C) Percentage of BrdU-positive cells with neuronal morphology in the p75NTR+/+ (control) versus p75NTR−/− (p75−/−) SCG at P3 and P4 (P = 0.4, n = 3 for each group). In both cases, error bars represent the standard error of the mean.

Mentions: Initially, we performed TUNEL to measure the total number of apoptotic cells within the sympathetic SCG on P2. To perform this analysis, every fourth section was collected, TdT-mediated dUTP-biotin nick end labeling (TUNEL) was performed, the positive nuclei were counted, and the number of positive profiles were multiplied by four to determine the total number of apoptotic nuclei per ganglia. As predicted, many TUNEL-positive nuclei were detected within the wild-type SCG; 1,472 ± 60 per ganglion (n = 3). In contrast, the p75NTR−/− SCG contained only 290 ± 45 apoptotic profiles per ganglion (n = 3), a statistically significant decrease of ∼80% (Fig. 1, A and B).


TrkA mediates developmental sympathetic neuron survival in vivo by silencing an ongoing p75NTR-mediated death signal.

Majdan M, Walsh GS, Aloyz R, Miller FD - J. Cell Biol. (2001)

The increase in sympathetic neuron number in the neonatal p75NTR−/− SCG is due to reduced apoptosis, not increased proliferation. (A) Fluorescence photomicrographs of TUNEL analysis of representative sections through the P2 SCG of p75NTR+/+ and p75NTR−/− animals. (B) Quantitation of TUNEL analysis similar to that seen in A. Numbers represent the total mean number of apoptotic nuclei in the SCG of p75NTR+/+ (control) versus p75NTR−/− (p75−/−) animals. (**P < 0.0005, n = 3). (C) Percentage of BrdU-positive cells with neuronal morphology in the p75NTR+/+ (control) versus p75NTR−/− (p75−/−) SCG at P3 and P4 (P = 0.4, n = 3 for each group). In both cases, error bars represent the standard error of the mean.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199335&req=5

fig1: The increase in sympathetic neuron number in the neonatal p75NTR−/− SCG is due to reduced apoptosis, not increased proliferation. (A) Fluorescence photomicrographs of TUNEL analysis of representative sections through the P2 SCG of p75NTR+/+ and p75NTR−/− animals. (B) Quantitation of TUNEL analysis similar to that seen in A. Numbers represent the total mean number of apoptotic nuclei in the SCG of p75NTR+/+ (control) versus p75NTR−/− (p75−/−) animals. (**P < 0.0005, n = 3). (C) Percentage of BrdU-positive cells with neuronal morphology in the p75NTR+/+ (control) versus p75NTR−/− (p75−/−) SCG at P3 and P4 (P = 0.4, n = 3 for each group). In both cases, error bars represent the standard error of the mean.
Mentions: Initially, we performed TUNEL to measure the total number of apoptotic cells within the sympathetic SCG on P2. To perform this analysis, every fourth section was collected, TdT-mediated dUTP-biotin nick end labeling (TUNEL) was performed, the positive nuclei were counted, and the number of positive profiles were multiplied by four to determine the total number of apoptotic nuclei per ganglia. As predicted, many TUNEL-positive nuclei were detected within the wild-type SCG; 1,472 ± 60 per ganglion (n = 3). In contrast, the p75NTR−/− SCG contained only 290 ± 45 apoptotic profiles per ganglion (n = 3), a statistically significant decrease of ∼80% (Fig. 1, A and B).

Bottom Line: A key question is whether p75NTR promotes apoptosis by directly inhibiting or modulating TrkA activity, or by stimulating cell death independently of TrkA.Here we provide evidence for the latter model.These data therefore support a model where developing sympathetic neurons are "destined to die" by an ongoing p75NTR-mediated apoptotic signal, and one of the major ways that TrkA promotes neuronal survival is by silencing this ongoing death signal.

View Article: PubMed Central - PubMed

Affiliation: Center for Neuronal Survival, Montreal Neurological Institute, McGill University, Montreal, Canada H3A 2B4.

ABSTRACT
Developmental sympathetic neuron death is determined by functional interactions between the TrkA/NGF receptor and the p75 neurotrophin receptor (p75NTR). A key question is whether p75NTR promotes apoptosis by directly inhibiting or modulating TrkA activity, or by stimulating cell death independently of TrkA. Here we provide evidence for the latter model. Specifically, experiments presented here demonstrate that the presence or absence of p75NTR does not alter Trk activity or NGF- and NT-3-mediated downstream survival signaling in primary neurons. Crosses of p75NTR-/- and TrkA-/- mice indicate that the coincident absence of p75NTR substantially rescues TrkA-/- sympathetic neurons from developmental death in vivo. Thus, p75NTR induces death regardless of the presence or absence of TrkA expression. These data therefore support a model where developing sympathetic neurons are "destined to die" by an ongoing p75NTR-mediated apoptotic signal, and one of the major ways that TrkA promotes neuronal survival is by silencing this ongoing death signal.

Show MeSH
Related in: MedlinePlus