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Transgenic activation of Ras in neurons promotes hypertrophy and protects from lesion-induced degeneration.

Heumann R, Goemans C, Bartsch D, Lingenhöhl K, Waldmeier PC, Hengerer B, Allegrini PR, Schellander K, Wagner EF, Arendt T, Kamdem RH, Obst-Pernberg K, Narz F, Wahle P, Berns H - J. Cell Biol. (2000)

Bottom Line: Neuronal Ras activation did not alter the total number of neurons, but induced cell soma hypertrophy, which resulted in a 14.5% increase of total brain volume.Choline acetyltransferase and tyrosine hydroxylase activities were increased, as well as neuropeptide Y expression.Neuronal Ras activation might become a tool to stabilize donor neurons for neural transplantation and to protect neuronal populations in neurodegenerative diseases.

View Article: PubMed Central - PubMed

Affiliation: Ruhr-University of Bochum, Molecular Neurobiochemistry, Germany. rolf.heumann@ruhr-uni-bochum.de

ABSTRACT
Ras is a universal eukaryotic intracellular protein integrating extracellular signals from multiple receptor types. To investigate its role in the adult central nervous system, constitutively activated V12-Ha-Ras was expressed selectively in neurons of transgenic mice via a synapsin promoter. Ras-transgene protein expression increased postnatally, reaching a four- to fivefold elevation at day 40 and persisting at this level, thereafter. Neuronal Ras was constitutively active and a corresponding activating phosphorylation of mitogen-activated kinase was observed, but there were no changes in the activity of phosphoinositide 3-kinase, the phosphorylation of its target kinase Akt/PKB, or expression of the anti-apoptotic proteins Bcl-2 or Bcl-X(L). Neuronal Ras activation did not alter the total number of neurons, but induced cell soma hypertrophy, which resulted in a 14.5% increase of total brain volume. Choline acetyltransferase and tyrosine hydroxylase activities were increased, as well as neuropeptide Y expression. Degeneration of motorneurons was completely prevented after facial nerve lesion in Ras-transgenic mice. Furthermore, neurotoxin-induced degeneration of dopaminergic substantia nigra neurons and their striatal projections was greatly attenuated. Thus, the Ras signaling pathway mimics neurotrophic effects and triggers neuroprotective mechanisms in adult mice. Neuronal Ras activation might become a tool to stabilize donor neurons for neural transplantation and to protect neuronal populations in neurodegenerative diseases.

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Protection of facial motorneurons from axotomy-induced degeneration. (A) Representative Nissl-stained sections of axotomized mice. The ipsilateral section of the wt mouse shows loss of facial motorneurons compared with the contralateral section, whereas the facial motorneuron number of the synRas-TG mouse remains equal on both sides. Arrowheads indicate well-preserved motorneurons with nucleoli in lesioned synRas-TG mice. Bar, 50 μm. (B) The number of facial motorneurons per section. Facial motorneurons of one out of three sections were counted. The first section is determined by the appearance of the first counted facial motorneuron. For better visualization, the ipsilateral distribution curve was centered within the contralateral distribution curve. Determination of wt facial motorneuron numbers reveals severe axotomy-induced degeneration along the total ipsilateral nucleus length, which cannot be detected in the synRas-TG mice. (C) The number of counted facial motorneurons per nucleus. Facial motorneurons of one out of three sections were counted. Total numbers of facial motorneurons per nucleus were not extrapolated. Analysis of counted facial motorneuron numbers reveals full protection of facial motorneurons from axotomy-induced degeneration by the transgene.
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Figure 6: Protection of facial motorneurons from axotomy-induced degeneration. (A) Representative Nissl-stained sections of axotomized mice. The ipsilateral section of the wt mouse shows loss of facial motorneurons compared with the contralateral section, whereas the facial motorneuron number of the synRas-TG mouse remains equal on both sides. Arrowheads indicate well-preserved motorneurons with nucleoli in lesioned synRas-TG mice. Bar, 50 μm. (B) The number of facial motorneurons per section. Facial motorneurons of one out of three sections were counted. The first section is determined by the appearance of the first counted facial motorneuron. For better visualization, the ipsilateral distribution curve was centered within the contralateral distribution curve. Determination of wt facial motorneuron numbers reveals severe axotomy-induced degeneration along the total ipsilateral nucleus length, which cannot be detected in the synRas-TG mice. (C) The number of counted facial motorneurons per nucleus. Facial motorneurons of one out of three sections were counted. Total numbers of facial motorneurons per nucleus were not extrapolated. Analysis of counted facial motorneuron numbers reveals full protection of facial motorneurons from axotomy-induced degeneration by the transgene.

Mentions: To test whether the Ras activation not only prevents embryonic apoptosis (see Introduction), but also promotes protection against lesion-induced neuronal degeneration, we performed facial nerve lesions in young-adult mice (10 wk old). There was on average a 34% reduction in cell number of wt mice, whereas there was no reduction (3%, not significant) in the synRas-TG littermates, as shown by counting the number of nucleoli-containing neurons in every third section of the facial nuclei from five mice each (Fig. 6b and Fig. c). Morphologically, neurons appeared healthy on the lesioned side, with no signs of degeneration or shrinkage in synRas-TG mice (Fig. 6 A).


Transgenic activation of Ras in neurons promotes hypertrophy and protects from lesion-induced degeneration.

Heumann R, Goemans C, Bartsch D, Lingenhöhl K, Waldmeier PC, Hengerer B, Allegrini PR, Schellander K, Wagner EF, Arendt T, Kamdem RH, Obst-Pernberg K, Narz F, Wahle P, Berns H - J. Cell Biol. (2000)

Protection of facial motorneurons from axotomy-induced degeneration. (A) Representative Nissl-stained sections of axotomized mice. The ipsilateral section of the wt mouse shows loss of facial motorneurons compared with the contralateral section, whereas the facial motorneuron number of the synRas-TG mouse remains equal on both sides. Arrowheads indicate well-preserved motorneurons with nucleoli in lesioned synRas-TG mice. Bar, 50 μm. (B) The number of facial motorneurons per section. Facial motorneurons of one out of three sections were counted. The first section is determined by the appearance of the first counted facial motorneuron. For better visualization, the ipsilateral distribution curve was centered within the contralateral distribution curve. Determination of wt facial motorneuron numbers reveals severe axotomy-induced degeneration along the total ipsilateral nucleus length, which cannot be detected in the synRas-TG mice. (C) The number of counted facial motorneurons per nucleus. Facial motorneurons of one out of three sections were counted. Total numbers of facial motorneurons per nucleus were not extrapolated. Analysis of counted facial motorneuron numbers reveals full protection of facial motorneurons from axotomy-induced degeneration by the transgene.
© Copyright Policy
Related In: Results  -  Collection

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Figure 6: Protection of facial motorneurons from axotomy-induced degeneration. (A) Representative Nissl-stained sections of axotomized mice. The ipsilateral section of the wt mouse shows loss of facial motorneurons compared with the contralateral section, whereas the facial motorneuron number of the synRas-TG mouse remains equal on both sides. Arrowheads indicate well-preserved motorneurons with nucleoli in lesioned synRas-TG mice. Bar, 50 μm. (B) The number of facial motorneurons per section. Facial motorneurons of one out of three sections were counted. The first section is determined by the appearance of the first counted facial motorneuron. For better visualization, the ipsilateral distribution curve was centered within the contralateral distribution curve. Determination of wt facial motorneuron numbers reveals severe axotomy-induced degeneration along the total ipsilateral nucleus length, which cannot be detected in the synRas-TG mice. (C) The number of counted facial motorneurons per nucleus. Facial motorneurons of one out of three sections were counted. Total numbers of facial motorneurons per nucleus were not extrapolated. Analysis of counted facial motorneuron numbers reveals full protection of facial motorneurons from axotomy-induced degeneration by the transgene.
Mentions: To test whether the Ras activation not only prevents embryonic apoptosis (see Introduction), but also promotes protection against lesion-induced neuronal degeneration, we performed facial nerve lesions in young-adult mice (10 wk old). There was on average a 34% reduction in cell number of wt mice, whereas there was no reduction (3%, not significant) in the synRas-TG littermates, as shown by counting the number of nucleoli-containing neurons in every third section of the facial nuclei from five mice each (Fig. 6b and Fig. c). Morphologically, neurons appeared healthy on the lesioned side, with no signs of degeneration or shrinkage in synRas-TG mice (Fig. 6 A).

Bottom Line: Neuronal Ras activation did not alter the total number of neurons, but induced cell soma hypertrophy, which resulted in a 14.5% increase of total brain volume.Choline acetyltransferase and tyrosine hydroxylase activities were increased, as well as neuropeptide Y expression.Neuronal Ras activation might become a tool to stabilize donor neurons for neural transplantation and to protect neuronal populations in neurodegenerative diseases.

View Article: PubMed Central - PubMed

Affiliation: Ruhr-University of Bochum, Molecular Neurobiochemistry, Germany. rolf.heumann@ruhr-uni-bochum.de

ABSTRACT
Ras is a universal eukaryotic intracellular protein integrating extracellular signals from multiple receptor types. To investigate its role in the adult central nervous system, constitutively activated V12-Ha-Ras was expressed selectively in neurons of transgenic mice via a synapsin promoter. Ras-transgene protein expression increased postnatally, reaching a four- to fivefold elevation at day 40 and persisting at this level, thereafter. Neuronal Ras was constitutively active and a corresponding activating phosphorylation of mitogen-activated kinase was observed, but there were no changes in the activity of phosphoinositide 3-kinase, the phosphorylation of its target kinase Akt/PKB, or expression of the anti-apoptotic proteins Bcl-2 or Bcl-X(L). Neuronal Ras activation did not alter the total number of neurons, but induced cell soma hypertrophy, which resulted in a 14.5% increase of total brain volume. Choline acetyltransferase and tyrosine hydroxylase activities were increased, as well as neuropeptide Y expression. Degeneration of motorneurons was completely prevented after facial nerve lesion in Ras-transgenic mice. Furthermore, neurotoxin-induced degeneration of dopaminergic substantia nigra neurons and their striatal projections was greatly attenuated. Thus, the Ras signaling pathway mimics neurotrophic effects and triggers neuroprotective mechanisms in adult mice. Neuronal Ras activation might become a tool to stabilize donor neurons for neural transplantation and to protect neuronal populations in neurodegenerative diseases.

Show MeSH
Related in: MedlinePlus