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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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Analysis of sympathetic neuron number in TrkA+/+, TrkA+/−, and TrkA−/− SCG. (A) Sympathetic neuron number in the SCG of TrkA+/+, TrkA+/−, and TrkA−/− animals at ages P1–P3 and P4–P6 in the C129/C57BL6 background. Results represent mean ± standard error (n = 3–5 for each genotype). At both ages, TrkA−/− neuron number is greatly decreased (**P < 0.005), but there is no significant difference in the TrkA+/− ganglia. (B) Western blot analysis of equal amounts of protein from the TrkA+/+ and TrkA+/− SCG at P10. Blots were probed for TrkA, TrkC, and tubulin.
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fig5: Analysis of sympathetic neuron number in TrkA+/+, TrkA+/−, and TrkA−/− SCG. (A) Sympathetic neuron number in the SCG of TrkA+/+, TrkA+/−, and TrkA−/− animals at ages P1–P3 and P4–P6 in the C129/C57BL6 background. Results represent mean ± standard error (n = 3–5 for each genotype). At both ages, TrkA−/− neuron number is greatly decreased (**P < 0.005), but there is no significant difference in the TrkA+/− ganglia. (B) Western blot analysis of equal amounts of protein from the TrkA+/+ and TrkA+/− SCG at P10. Blots were probed for TrkA, TrkC, and tubulin.

Mentions: We then characterized neuronal numbers in the SCG of the p75NTR+/+, TrkA+/+, TrkA+/−, and TrkA−/− animals over this same time frame. This analysis revealed that, as previously reported (Fagan et al., 1996), there was a dramatic decrease in the number of SCG neurons at P1–P3 in the TrkA−/− animals relative to their TrkA+/+ littermates (6,108 ± 411, n = 3 versus 16,390 ± 1,003, n = 5). By P4–P6, the neuronal loss in the TrkA−/− SCGs was even more substantial (3,557 ± 724, n = 3 versus 18,211 ± 1,401, n = 4) (Fig. 5 A). These numbers represent a 63 and 80% decrease in neuronal number in the TrkA−/− ganglia at P1–P3 and P4–P6, respectively.


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)

Analysis of sympathetic neuron number in TrkA+/+, TrkA+/−, and TrkA−/− SCG. (A) Sympathetic neuron number in the SCG of TrkA+/+, TrkA+/−, and TrkA−/− animals at ages P1–P3 and P4–P6 in the C129/C57BL6 background. Results represent mean ± standard error (n = 3–5 for each genotype). At both ages, TrkA−/− neuron number is greatly decreased (**P < 0.005), but there is no significant difference in the TrkA+/− ganglia. (B) Western blot analysis of equal amounts of protein from the TrkA+/+ and TrkA+/− SCG at P10. Blots were probed for TrkA, TrkC, and tubulin.
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Related In: Results  -  Collection

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

fig5: Analysis of sympathetic neuron number in TrkA+/+, TrkA+/−, and TrkA−/− SCG. (A) Sympathetic neuron number in the SCG of TrkA+/+, TrkA+/−, and TrkA−/− animals at ages P1–P3 and P4–P6 in the C129/C57BL6 background. Results represent mean ± standard error (n = 3–5 for each genotype). At both ages, TrkA−/− neuron number is greatly decreased (**P < 0.005), but there is no significant difference in the TrkA+/− ganglia. (B) Western blot analysis of equal amounts of protein from the TrkA+/+ and TrkA+/− SCG at P10. Blots were probed for TrkA, TrkC, and tubulin.
Mentions: We then characterized neuronal numbers in the SCG of the p75NTR+/+, TrkA+/+, TrkA+/−, and TrkA−/− animals over this same time frame. This analysis revealed that, as previously reported (Fagan et al., 1996), there was a dramatic decrease in the number of SCG neurons at P1–P3 in the TrkA−/− animals relative to their TrkA+/+ littermates (6,108 ± 411, n = 3 versus 16,390 ± 1,003, n = 5). By P4–P6, the neuronal loss in the TrkA−/− SCGs was even more substantial (3,557 ± 724, n = 3 versus 18,211 ± 1,401, n = 4) (Fig. 5 A). These numbers represent a 63 and 80% decrease in neuronal number in the TrkA−/− ganglia at P1–P3 and P4–P6, respectively.

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