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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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p75NTR−/−, TrkA−/− sympathetic neurons express neuron-specific βIII-tubulin and tyrosine hydroxylase. Photomicrographs of alternate sections taken from a p75NTR−/−, TrkA−/− ganglia and then either Nissl-stained or immunostained for the neuron-specific protein βIII-tubulin or for tyrosine hydroxylase (TH). The upper panels are low-power micrographs of entire sections, and the bottom panels are high-power micrographs showing stained neurons (arrows).
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fig7: p75NTR−/−, TrkA−/− sympathetic neurons express neuron-specific βIII-tubulin and tyrosine hydroxylase. Photomicrographs of alternate sections taken from a p75NTR−/−, TrkA−/− ganglia and then either Nissl-stained or immunostained for the neuron-specific protein βIII-tubulin or for tyrosine hydroxylase (TH). The upper panels are low-power micrographs of entire sections, and the bottom panels are high-power micrographs showing stained neurons (arrows).

Mentions: In spite of the increase in neuron number, double mutant animals were not healthier than TrkA−/− animals, and most died within the first three postnatal days. Moreover, cresyl violet–stained sections of P4 wild-type and TrkA−/−, p75NTR−/− SCGs showed that the rescued cells were much smaller than their wild-type counterparts, a phenotype similar to that previously reported for sympathetic neurons lacking other components of the cell death machinery, such as Bax−/− cells (Deckwerth et al., 1996). To ensure that these smaller cells were in fact neurons, we immunostained sections from P2 TrkA−/−, p75NTR−/− SCGs with an antibody for neuron-specific βIII-tubulin, and then Nissl-stained the alternate sections (Fig. 7). This analysis revealed that all of the smaller neuronal cells expressed βIII-tubulin, and that the numbers of neurons obtained by counting the immunostained versus Nissl-stained sections were similar: in two different p75NTR−/−, TrkA−/− SCGs, 790 and 1032 cresyl violet–stained neurons were present in representative sections, and 930 and 808 βIII tubulin-positive cells were present in the adjacent sections, respectively. We also immunostained alternate sections from the same animals for tyrosine hydroxylase (Fig. 7). Whereas there was significantly more variability in tyrosine hydroxylase levels from cell to cell, likely as a consequence of the fact that tyrosine hydroxylase levels are highly upregulated by Trk signaling, this analysis confirmed that the small, βIII-tubulin–positive cells were sympathetic neurons (Fig. 7). Thus, although the absence of p75NTR significantly rescued and/or delayed the cell death that occurs in the absence of TrkA signaling, it was unable to rescue other TrkA-dependent phenotypes, such as cell body hypertrophy and, presumably, target innervation.


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)

p75NTR−/−, TrkA−/− sympathetic neurons express neuron-specific βIII-tubulin and tyrosine hydroxylase. Photomicrographs of alternate sections taken from a p75NTR−/−, TrkA−/− ganglia and then either Nissl-stained or immunostained for the neuron-specific protein βIII-tubulin or for tyrosine hydroxylase (TH). The upper panels are low-power micrographs of entire sections, and the bottom panels are high-power micrographs showing stained neurons (arrows).
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Related In: Results  -  Collection

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fig7: p75NTR−/−, TrkA−/− sympathetic neurons express neuron-specific βIII-tubulin and tyrosine hydroxylase. Photomicrographs of alternate sections taken from a p75NTR−/−, TrkA−/− ganglia and then either Nissl-stained or immunostained for the neuron-specific protein βIII-tubulin or for tyrosine hydroxylase (TH). The upper panels are low-power micrographs of entire sections, and the bottom panels are high-power micrographs showing stained neurons (arrows).
Mentions: In spite of the increase in neuron number, double mutant animals were not healthier than TrkA−/− animals, and most died within the first three postnatal days. Moreover, cresyl violet–stained sections of P4 wild-type and TrkA−/−, p75NTR−/− SCGs showed that the rescued cells were much smaller than their wild-type counterparts, a phenotype similar to that previously reported for sympathetic neurons lacking other components of the cell death machinery, such as Bax−/− cells (Deckwerth et al., 1996). To ensure that these smaller cells were in fact neurons, we immunostained sections from P2 TrkA−/−, p75NTR−/− SCGs with an antibody for neuron-specific βIII-tubulin, and then Nissl-stained the alternate sections (Fig. 7). This analysis revealed that all of the smaller neuronal cells expressed βIII-tubulin, and that the numbers of neurons obtained by counting the immunostained versus Nissl-stained sections were similar: in two different p75NTR−/−, TrkA−/− SCGs, 790 and 1032 cresyl violet–stained neurons were present in representative sections, and 930 and 808 βIII tubulin-positive cells were present in the adjacent sections, respectively. We also immunostained alternate sections from the same animals for tyrosine hydroxylase (Fig. 7). Whereas there was significantly more variability in tyrosine hydroxylase levels from cell to cell, likely as a consequence of the fact that tyrosine hydroxylase levels are highly upregulated by Trk signaling, this analysis confirmed that the small, βIII-tubulin–positive cells were sympathetic neurons (Fig. 7). Thus, although the absence of p75NTR significantly rescued and/or delayed the cell death that occurs in the absence of TrkA signaling, it was unable to rescue other TrkA-dependent phenotypes, such as cell body hypertrophy and, presumably, target innervation.

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