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p53 is essential for developmental neuron death as regulated by the TrkA and p75 neurotrophin receptors.

Aloyz RS, Bamji SX, Pozniak CD, Toma JG, Atwal J, Kaplan DR, Miller FD - J. Cell Biol. (1998)

Bottom Line: NGF withdrawal also results in elevation of a known p53 target, the apoptotic protein Bax.Finally, when p53 levels are reduced or absent in p53+/- or p53-/- mice, naturally occurring sympathetic neuron death is inhibited.Thus, p53 is an essential common component of two receptor-mediated signal transduction cascades that converge on the MEKK-JNK pathway to regulate the developmental death of sympathetic neurons.

View Article: PubMed Central - PubMed

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

ABSTRACT
Naturally occurring sympathetic neuron death is the result of two apoptotic signaling events: one normally suppressed by NGF/TrkA survival signals, and a second activated by the p75 neurotrophin receptor. Here we demonstrate that the p53 tumor suppressor protein, likely as induced by the MEKK-JNK pathway, is an essential component of both of these apoptotic signaling cascades. In cultured neonatal sympathetic neurons, p53 protein levels are elevated in response to both NGF withdrawal and p75NTR activation. NGF withdrawal also results in elevation of a known p53 target, the apoptotic protein Bax. Functional ablation of p53 using the adenovirus E1B55K protein inhibits neuronal apoptosis as induced by either NGF withdrawal or p75 activation. Direct stimulation of the MEKK-JNK pathway using activated MEKK1 has similar effects; p53 and Bax are increased and the subsequent neuronal apoptosis can be rescued by E1B55K. Expression of p53 in sympathetic neurons indicates that p53 functions downstream of JNK and upstream of Bax. Finally, when p53 levels are reduced or absent in p53+/- or p53-/- mice, naturally occurring sympathetic neuron death is inhibited. Thus, p53 is an essential common component of two receptor-mediated signal transduction cascades that converge on the MEKK-JNK pathway to regulate the developmental death of sympathetic neurons.

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The number of sympathetic neurons in the superior  cervical ganglia is increased when p53 levels are decreased in  vivo. (A) Photomicrographs of cresyl-violet stained sections  through the SCG of wild-type (p53+/+) versus p53+/− mice of  the same genetic background at postnatal day 15, when naturally  occurring sympathetic neuron death is complete. (B) Fluorescent  photomicrographs of in situ TUNEL labeling in the SCG of  p53+/+ versus p53+/− mice of the same genetic background at  postnatal day 7, when developmental sympathetic neuron death  is ongoing. (C) The number of TUNEL-positive cells in the SCG  of P7 mice that are heterozygous (p53+/−) or wild-type  (p53+/+) for a p53 mutation created by homologous recombination (Donehower et al., 1992). Results are expressed as the  mean ± standard error of the total number of TUNEL-positive  cells per SCG (n = 5 for p53+/− andn = 4 for p53+/+). **Indicates that these two values are significantly different (P = 0.016).  (D) The number of neurons in the SCG of P1 or P15 mice that  are either p53+/+ (control), or heterozygous (p53+/−) or homozygous (p53−/−) for the p53 mutant allele. Results are expressed as the mean ± standard error (n = 3 for P1 p53+/+, 5 for  P1 p53+/−, 3 for P1 p53−/−, 5 for P15 p53+/+, 6 for P15 p53+/−  and 3 for P15 p53−/−). **Indicates values significantly different  from p53+/+ SCG of the same age (P < 0.05). Note that while  there is a statistically significant loss of 45% of the neurons in the  p53+/+ SCG over this time period (**P < 0.05), there is no significant loss of neurons in either the p53+/− or p53−/− SCG  (P > 0.3).
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Figure 6: The number of sympathetic neurons in the superior cervical ganglia is increased when p53 levels are decreased in vivo. (A) Photomicrographs of cresyl-violet stained sections through the SCG of wild-type (p53+/+) versus p53+/− mice of the same genetic background at postnatal day 15, when naturally occurring sympathetic neuron death is complete. (B) Fluorescent photomicrographs of in situ TUNEL labeling in the SCG of p53+/+ versus p53+/− mice of the same genetic background at postnatal day 7, when developmental sympathetic neuron death is ongoing. (C) The number of TUNEL-positive cells in the SCG of P7 mice that are heterozygous (p53+/−) or wild-type (p53+/+) for a p53 mutation created by homologous recombination (Donehower et al., 1992). Results are expressed as the mean ± standard error of the total number of TUNEL-positive cells per SCG (n = 5 for p53+/− andn = 4 for p53+/+). **Indicates that these two values are significantly different (P = 0.016). (D) The number of neurons in the SCG of P1 or P15 mice that are either p53+/+ (control), or heterozygous (p53+/−) or homozygous (p53−/−) for the p53 mutant allele. Results are expressed as the mean ± standard error (n = 3 for P1 p53+/+, 5 for P1 p53+/−, 3 for P1 p53−/−, 5 for P15 p53+/+, 6 for P15 p53+/− and 3 for P15 p53−/−). **Indicates values significantly different from p53+/+ SCG of the same age (P < 0.05). Note that while there is a statistically significant loss of 45% of the neurons in the p53+/+ SCG over this time period (**P < 0.05), there is no significant loss of neurons in either the p53+/− or p53−/− SCG (P > 0.3).

Mentions: Our previous work indicates that naturally occurring sympathetic neuron death is a result both of suboptimal activation of the TrkA receptor and of coincident activation of p75NTR (Bamji et al., 1998). Since, in culture, both of these types of neuronal apoptosis require p53, we hypothesized that p53 would also be essential for sympathetic neuron death in vivo. To test this hypothesis, we examined the SCG of transgenic mice in which the p53 gene was deleted by homologous recombination (Donehower et al., 1992). In control mice, the SCG contains ∼20,000–25,000 neurons at birth, depending on the genetic background. Over the ensuing two weeks approximately half of these neurons are lost so that by P15, control SCGs contain ∼13,000 neurons (Bamji et al., 1998). We therefore chose to analyze the SCG from p53+/+, p53+/− and p53−/− mice at two timepoints; postnatal days 1 and 15, timepoints immediately preceding and after the normal period of naturally occurring cell death (Fig. 6, A and D).


p53 is essential for developmental neuron death as regulated by the TrkA and p75 neurotrophin receptors.

Aloyz RS, Bamji SX, Pozniak CD, Toma JG, Atwal J, Kaplan DR, Miller FD - J. Cell Biol. (1998)

The number of sympathetic neurons in the superior  cervical ganglia is increased when p53 levels are decreased in  vivo. (A) Photomicrographs of cresyl-violet stained sections  through the SCG of wild-type (p53+/+) versus p53+/− mice of  the same genetic background at postnatal day 15, when naturally  occurring sympathetic neuron death is complete. (B) Fluorescent  photomicrographs of in situ TUNEL labeling in the SCG of  p53+/+ versus p53+/− mice of the same genetic background at  postnatal day 7, when developmental sympathetic neuron death  is ongoing. (C) The number of TUNEL-positive cells in the SCG  of P7 mice that are heterozygous (p53+/−) or wild-type  (p53+/+) for a p53 mutation created by homologous recombination (Donehower et al., 1992). Results are expressed as the  mean ± standard error of the total number of TUNEL-positive  cells per SCG (n = 5 for p53+/− andn = 4 for p53+/+). **Indicates that these two values are significantly different (P = 0.016).  (D) The number of neurons in the SCG of P1 or P15 mice that  are either p53+/+ (control), or heterozygous (p53+/−) or homozygous (p53−/−) for the p53 mutant allele. Results are expressed as the mean ± standard error (n = 3 for P1 p53+/+, 5 for  P1 p53+/−, 3 for P1 p53−/−, 5 for P15 p53+/+, 6 for P15 p53+/−  and 3 for P15 p53−/−). **Indicates values significantly different  from p53+/+ SCG of the same age (P < 0.05). Note that while  there is a statistically significant loss of 45% of the neurons in the  p53+/+ SCG over this time period (**P < 0.05), there is no significant loss of neurons in either the p53+/− or p53−/− SCG  (P > 0.3).
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Figure 6: The number of sympathetic neurons in the superior cervical ganglia is increased when p53 levels are decreased in vivo. (A) Photomicrographs of cresyl-violet stained sections through the SCG of wild-type (p53+/+) versus p53+/− mice of the same genetic background at postnatal day 15, when naturally occurring sympathetic neuron death is complete. (B) Fluorescent photomicrographs of in situ TUNEL labeling in the SCG of p53+/+ versus p53+/− mice of the same genetic background at postnatal day 7, when developmental sympathetic neuron death is ongoing. (C) The number of TUNEL-positive cells in the SCG of P7 mice that are heterozygous (p53+/−) or wild-type (p53+/+) for a p53 mutation created by homologous recombination (Donehower et al., 1992). Results are expressed as the mean ± standard error of the total number of TUNEL-positive cells per SCG (n = 5 for p53+/− andn = 4 for p53+/+). **Indicates that these two values are significantly different (P = 0.016). (D) The number of neurons in the SCG of P1 or P15 mice that are either p53+/+ (control), or heterozygous (p53+/−) or homozygous (p53−/−) for the p53 mutant allele. Results are expressed as the mean ± standard error (n = 3 for P1 p53+/+, 5 for P1 p53+/−, 3 for P1 p53−/−, 5 for P15 p53+/+, 6 for P15 p53+/− and 3 for P15 p53−/−). **Indicates values significantly different from p53+/+ SCG of the same age (P < 0.05). Note that while there is a statistically significant loss of 45% of the neurons in the p53+/+ SCG over this time period (**P < 0.05), there is no significant loss of neurons in either the p53+/− or p53−/− SCG (P > 0.3).
Mentions: Our previous work indicates that naturally occurring sympathetic neuron death is a result both of suboptimal activation of the TrkA receptor and of coincident activation of p75NTR (Bamji et al., 1998). Since, in culture, both of these types of neuronal apoptosis require p53, we hypothesized that p53 would also be essential for sympathetic neuron death in vivo. To test this hypothesis, we examined the SCG of transgenic mice in which the p53 gene was deleted by homologous recombination (Donehower et al., 1992). In control mice, the SCG contains ∼20,000–25,000 neurons at birth, depending on the genetic background. Over the ensuing two weeks approximately half of these neurons are lost so that by P15, control SCGs contain ∼13,000 neurons (Bamji et al., 1998). We therefore chose to analyze the SCG from p53+/+, p53+/− and p53−/− mice at two timepoints; postnatal days 1 and 15, timepoints immediately preceding and after the normal period of naturally occurring cell death (Fig. 6, A and D).

Bottom Line: NGF withdrawal also results in elevation of a known p53 target, the apoptotic protein Bax.Finally, when p53 levels are reduced or absent in p53+/- or p53-/- mice, naturally occurring sympathetic neuron death is inhibited.Thus, p53 is an essential common component of two receptor-mediated signal transduction cascades that converge on the MEKK-JNK pathway to regulate the developmental death of sympathetic neurons.

View Article: PubMed Central - PubMed

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

ABSTRACT
Naturally occurring sympathetic neuron death is the result of two apoptotic signaling events: one normally suppressed by NGF/TrkA survival signals, and a second activated by the p75 neurotrophin receptor. Here we demonstrate that the p53 tumor suppressor protein, likely as induced by the MEKK-JNK pathway, is an essential component of both of these apoptotic signaling cascades. In cultured neonatal sympathetic neurons, p53 protein levels are elevated in response to both NGF withdrawal and p75NTR activation. NGF withdrawal also results in elevation of a known p53 target, the apoptotic protein Bax. Functional ablation of p53 using the adenovirus E1B55K protein inhibits neuronal apoptosis as induced by either NGF withdrawal or p75 activation. Direct stimulation of the MEKK-JNK pathway using activated MEKK1 has similar effects; p53 and Bax are increased and the subsequent neuronal apoptosis can be rescued by E1B55K. Expression of p53 in sympathetic neurons indicates that p53 functions downstream of JNK and upstream of Bax. Finally, when p53 levels are reduced or absent in p53+/- or p53-/- mice, naturally occurring sympathetic neuron death is inhibited. Thus, p53 is an essential common component of two receptor-mediated signal transduction cascades that converge on the MEKK-JNK pathway to regulate the developmental death of sympathetic neurons.

Show MeSH
Related in: MedlinePlus