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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 absence of p75NTR rescues the sympathetic neuron apoptosis observed in the neonatal TrkA−/− SCG. (A) Sympathetic neuron number in TrkA−/−, p75NTR+/+, p75NTR+/−, and p75NTR−/− SCG at P1–P3 and P4–P6. For comparison, TrkA+/+, p75NTR+/+ (WT) SCG counts are also shown. Results represent mean ± standard error (n = 3–5 for each genotype). In the absence of TrkA, the number of neurons is increased in the p75NTR−/− versus p75NTR+/+ SCG at both P1–P3 (**P < 0.0005) and P4–P6 (**P < 0.001). In addition, at both developmental ages, the number of neurons in p75NTR+/− SCG is significantly greater than in p75NTR+/+ SCG (*P < 0.05 for both groups). (B) Photomicrographs of cresyl violet–stained sections showing the morphology of SCG sympathetic neurons in p75NTR+/+, TrkA+/+ (left) and p75NTR−/−, TrkA−/− (right) mice at P4. Arrows indicate sympathetic neurons.
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fig6: The absence of p75NTR rescues the sympathetic neuron apoptosis observed in the neonatal TrkA−/− SCG. (A) Sympathetic neuron number in TrkA−/−, p75NTR+/+, p75NTR+/−, and p75NTR−/− SCG at P1–P3 and P4–P6. For comparison, TrkA+/+, p75NTR+/+ (WT) SCG counts are also shown. Results represent mean ± standard error (n = 3–5 for each genotype). In the absence of TrkA, the number of neurons is increased in the p75NTR−/− versus p75NTR+/+ SCG at both P1–P3 (**P < 0.0005) and P4–P6 (**P < 0.001). In addition, at both developmental ages, the number of neurons in p75NTR+/− SCG is significantly greater than in p75NTR+/+ SCG (*P < 0.05 for both groups). (B) Photomicrographs of cresyl violet–stained sections showing the morphology of SCG sympathetic neurons in p75NTR+/+, TrkA+/+ (left) and p75NTR−/−, TrkA−/− (right) mice at P4. Arrows indicate sympathetic neurons.

Mentions: Finally, we determined whether the absence of p75NTR was able to rescue the dramatic loss of sympathetic neurons observed in the TrkA−/− SCG. At P1–P3, the concomitant absence of p75NTR almost completely rescued sympathetic neuron numbers in the TrkA−/−, p75NTR−/− SCG; 13,665 ± 730 neurons (n = 3) versus 16,390 ± 1,003 neurons (n = 5) in the TrkA+/+, p75NTR+/+ SCG (Fig. 6 A). Moreover, at this age, even the loss of one p75NTR allele was enough to significantly increase neuronal survival; the TrkA−/−, p75NTR+/− SCG contained 11,000 neurons, whereas the TrkA−/−, p75NTR+/+ ganglia contained only 6,108 ± 411 neurons. A rescue was also observed at P4–P6. The magnitude was, however, lower than that seen at P1–P3; 9,861 ± 622 neurons (n = 5) versus 3,557 ± 724 neurons (n = 3) in the TrkA−/−, p75NTR+/+ SCG (Fig. 6 A). Similarly, a rescue was still observed in the TrkA−/−, p75NTR+/− ganglia at P4–P6, although this was of a lesser magnitude than that observed in the p75NTR−/− SCG. Thus, independent signaling via p75NTR represents a major default death pathway for developing sympathetic neurons.


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 absence of p75NTR rescues the sympathetic neuron apoptosis observed in the neonatal TrkA−/− SCG. (A) Sympathetic neuron number in TrkA−/−, p75NTR+/+, p75NTR+/−, and p75NTR−/− SCG at P1–P3 and P4–P6. For comparison, TrkA+/+, p75NTR+/+ (WT) SCG counts are also shown. Results represent mean ± standard error (n = 3–5 for each genotype). In the absence of TrkA, the number of neurons is increased in the p75NTR−/− versus p75NTR+/+ SCG at both P1–P3 (**P < 0.0005) and P4–P6 (**P < 0.001). In addition, at both developmental ages, the number of neurons in p75NTR+/− SCG is significantly greater than in p75NTR+/+ SCG (*P < 0.05 for both groups). (B) Photomicrographs of cresyl violet–stained sections showing the morphology of SCG sympathetic neurons in p75NTR+/+, TrkA+/+ (left) and p75NTR−/−, TrkA−/− (right) mice at P4. Arrows indicate sympathetic neurons.
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fig6: The absence of p75NTR rescues the sympathetic neuron apoptosis observed in the neonatal TrkA−/− SCG. (A) Sympathetic neuron number in TrkA−/−, p75NTR+/+, p75NTR+/−, and p75NTR−/− SCG at P1–P3 and P4–P6. For comparison, TrkA+/+, p75NTR+/+ (WT) SCG counts are also shown. Results represent mean ± standard error (n = 3–5 for each genotype). In the absence of TrkA, the number of neurons is increased in the p75NTR−/− versus p75NTR+/+ SCG at both P1–P3 (**P < 0.0005) and P4–P6 (**P < 0.001). In addition, at both developmental ages, the number of neurons in p75NTR+/− SCG is significantly greater than in p75NTR+/+ SCG (*P < 0.05 for both groups). (B) Photomicrographs of cresyl violet–stained sections showing the morphology of SCG sympathetic neurons in p75NTR+/+, TrkA+/+ (left) and p75NTR−/−, TrkA−/− (right) mice at P4. Arrows indicate sympathetic neurons.
Mentions: Finally, we determined whether the absence of p75NTR was able to rescue the dramatic loss of sympathetic neurons observed in the TrkA−/− SCG. At P1–P3, the concomitant absence of p75NTR almost completely rescued sympathetic neuron numbers in the TrkA−/−, p75NTR−/− SCG; 13,665 ± 730 neurons (n = 3) versus 16,390 ± 1,003 neurons (n = 5) in the TrkA+/+, p75NTR+/+ SCG (Fig. 6 A). Moreover, at this age, even the loss of one p75NTR allele was enough to significantly increase neuronal survival; the TrkA−/−, p75NTR+/− SCG contained 11,000 neurons, whereas the TrkA−/−, p75NTR+/+ ganglia contained only 6,108 ± 411 neurons. A rescue was also observed at P4–P6. The magnitude was, however, lower than that seen at P1–P3; 9,861 ± 622 neurons (n = 5) versus 3,557 ± 724 neurons (n = 3) in the TrkA−/−, p75NTR+/+ SCG (Fig. 6 A). Similarly, a rescue was still observed in the TrkA−/−, p75NTR+/− ganglia at P4–P6, although this was of a lesser magnitude than that observed in the p75NTR−/− SCG. Thus, independent signaling via p75NTR represents a major default death pathway for developing sympathetic neurons.

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