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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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Sympathetic neuron number is increased in the developing C129/C57Bl6 SCG as an inverse function of p75NTR gene dosage. Sympathetic neuron number in the SCG of p75NTR+/+, p75NTR+/−, and p75NTR−/− animals at ages P1–P3 and P4–P6. Results represent mean ± standard error (n = 3–7 for each genotype). At P1–P3, p75NTR+/+ and p75NTR−/− SCG numbers are significantly different (*P < 0.05), and at P4–P6, p75NTR+/+ neuron counts are significantly different from the p75NTR+/− and p75NTR−/− counts (*P < 0.05 for both groups). For comparison, neuronal numbers from the P4 SCG of p75NTR+/+ and p75NTR−/− C129 animals are shown (Bamji et al., 1998).
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fig4: Sympathetic neuron number is increased in the developing C129/C57Bl6 SCG as an inverse function of p75NTR gene dosage. Sympathetic neuron number in the SCG of p75NTR+/+, p75NTR+/−, and p75NTR−/− animals at ages P1–P3 and P4–P6. Results represent mean ± standard error (n = 3–7 for each genotype). At P1–P3, p75NTR+/+ and p75NTR−/− SCG numbers are significantly different (*P < 0.05), and at P4–P6, p75NTR+/+ neuron counts are significantly different from the p75NTR+/− and p75NTR−/− counts (*P < 0.05 for both groups). For comparison, neuronal numbers from the P4 SCG of p75NTR+/+ and p75NTR−/− C129 animals are shown (Bamji et al., 1998).

Mentions: To perform these studies, we initially confirmed the p75NTR−/− phenotype in the mixed C129/C57BL6 background that resulted from these crosses. TrkA+/− and p75NTR−/− animals were crossed, and then their TrkA+/−, p75NTR+/− progeny were bred to produce animals for analysis. The SCGs were analyzed from the resultant TrkA+/+, p75NTR+/+, p75NTR+/−, and p75NTR−/− animals; ganglia were grouped by age, P1–P3 and P4–P6. This analysis revealed an increase in the numbers of neurons in the p75NTR−/− versus p75NTR+/+ SCG at both ages (P1–P3: 21,425 ± 1,324, n = 3 versus 16,390 ± 1,003, n = 5, P < 0.05; P4–P6: 27,221 ± 3,570, n = 6 versus 18,211 ± 1,401, n = 4, P < 0.05) (Fig. 4), a phenotype similar to that observed in the C129 background (Bamji et al., 1998).


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)

Sympathetic neuron number is increased in the developing C129/C57Bl6 SCG as an inverse function of p75NTR gene dosage. Sympathetic neuron number in the SCG of p75NTR+/+, p75NTR+/−, and p75NTR−/− animals at ages P1–P3 and P4–P6. Results represent mean ± standard error (n = 3–7 for each genotype). At P1–P3, p75NTR+/+ and p75NTR−/− SCG numbers are significantly different (*P < 0.05), and at P4–P6, p75NTR+/+ neuron counts are significantly different from the p75NTR+/− and p75NTR−/− counts (*P < 0.05 for both groups). For comparison, neuronal numbers from the P4 SCG of p75NTR+/+ and p75NTR−/− C129 animals are shown (Bamji et al., 1998).
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Related In: Results  -  Collection

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

fig4: Sympathetic neuron number is increased in the developing C129/C57Bl6 SCG as an inverse function of p75NTR gene dosage. Sympathetic neuron number in the SCG of p75NTR+/+, p75NTR+/−, and p75NTR−/− animals at ages P1–P3 and P4–P6. Results represent mean ± standard error (n = 3–7 for each genotype). At P1–P3, p75NTR+/+ and p75NTR−/− SCG numbers are significantly different (*P < 0.05), and at P4–P6, p75NTR+/+ neuron counts are significantly different from the p75NTR+/− and p75NTR−/− counts (*P < 0.05 for both groups). For comparison, neuronal numbers from the P4 SCG of p75NTR+/+ and p75NTR−/− C129 animals are shown (Bamji et al., 1998).
Mentions: To perform these studies, we initially confirmed the p75NTR−/− phenotype in the mixed C129/C57BL6 background that resulted from these crosses. TrkA+/− and p75NTR−/− animals were crossed, and then their TrkA+/−, p75NTR+/− progeny were bred to produce animals for analysis. The SCGs were analyzed from the resultant TrkA+/+, p75NTR+/+, p75NTR+/−, and p75NTR−/− animals; ganglia were grouped by age, P1–P3 and P4–P6. This analysis revealed an increase in the numbers of neurons in the p75NTR−/− versus p75NTR+/+ SCG at both ages (P1–P3: 21,425 ± 1,324, n = 3 versus 16,390 ± 1,003, n = 5, P < 0.05; P4–P6: 27,221 ± 3,570, n = 6 versus 18,211 ± 1,401, n = 4, P < 0.05) (Fig. 4), a phenotype similar to that observed in the C129 background (Bamji et al., 1998).

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