Limits...
Conditional gene ablation of Stat3 reveals differential signaling requirements for survival of motoneurons during development and after nerve injury in the adult.

Schweizer U, Gunnersen J, Karch C, Wiese S, Holtmann B, Takeda K, Akira S, Sendtner M - J. Cell Biol. (2002)

Bottom Line: In contrast, motoneuron survival is significantly reduced after facial nerve lesion in the adult.Stat3 is essential for upregulation of Reg-2 and Bcl-xl expression in lesioned motoneurons.Our data show that Stat3 activation plays an essential role for motoneuron survival after nerve lesion in postnatal life but not during embryonic development, indicating that signaling requirements for motoneuron survival change during maturation.

View Article: PubMed Central - PubMed

Affiliation: Institute for Clinical Neurobiology, University of Würzburg, 97080 Würzburg, Germany.

ABSTRACT
Members of the ciliary neurotrophic factor (CNTF)/leukemia inhibitory factor (LIF)/cardiotrophin gene family are potent survival factors for embryonic and lesioned motoneurons. These factors act via receptor complexes involving gp130 and LIFR-beta and ligand binding leads to activation of various signaling pathways, including phosphorylation of Stat3. The role of Stat3 in neuronal survival was investigated in mice by Cre-mediated gene ablation in motoneurons. Cre is expressed under the neurofilament light chain (NF-L) promoter, starting around E12 when these neurons become dependent on neurotrophic support. Loss of motoneurons during the embryonic period of naturally occurring cell death is not enhanced in NF-L-Cre; Stat3(flox/KO) mice although motoneurons isolated from these mice need higher concentrations of CNTF for maximal survival in culture. In contrast, motoneuron survival is significantly reduced after facial nerve lesion in the adult. These neurons, however, can be rescued by the addition of neurotrophic factors, including CNTF. Stat3 is essential for upregulation of Reg-2 and Bcl-xl expression in lesioned motoneurons. Our data show that Stat3 activation plays an essential role for motoneuron survival after nerve lesion in postnatal life but not during embryonic development, indicating that signaling requirements for motoneuron survival change during maturation.

Show MeSH

Related in: MedlinePlus

Beneficial effect of GDNF and CNTF on the survival of axotomized NF-L–Cre; Stat3flox/KO motoneurons. CNTF and GDNF rescued >50% of otherwise degenerated motoneurons, whereas the effect of BDNF was not significant. Motoneurons were counted in serial sections through the brain stem and statistical analysis was performed using ANOVA with Bonferroni's post hoc comparison. Single asterisk indicates P < 0.05; double asterisk indicates P < 0.01; triple asterisk indicates P < 0.001.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2199226&req=5

fig4: Beneficial effect of GDNF and CNTF on the survival of axotomized NF-L–Cre; Stat3flox/KO motoneurons. CNTF and GDNF rescued >50% of otherwise degenerated motoneurons, whereas the effect of BDNF was not significant. Motoneurons were counted in serial sections through the brain stem and statistical analysis was performed using ANOVA with Bonferroni's post hoc comparison. Single asterisk indicates P < 0.05; double asterisk indicates P < 0.01; triple asterisk indicates P < 0.001.

Mentions: Transection of the facial nerve in newborn mice leads to degeneration of more than 80% of the corresponding motoneurons. These neurons can be rescued by local administration of neurotrophic factors (Sendtner et al., 1990, 1992; Henderson et al., 1994). To test whether this survival response is impaired in the absence of Stat3, GDNF and BDNF were locally administered to the lesioned facial nerve in 4-wk-old NF-L–Cre; Stat3flox/KO and NF-L–Cre; Stat3flox/wt mice. GDNF was most potent in NF-L–Cre; Stat3flox/KO animals and increased motoneuron survival to 86 ± 2% (n = 4, P < 0.01 compared with untreated control) at 2 wk after axotomy (Fig. 4) . BDNF application led to an increase in the number of surviving motoneurons from 57 ± 6% (n = 6) to 67 ± 6% (n = 5) that did not reach statistical significance (Fig. 4). We also applied CNTF to the proximal nerve stump in NF-L–Cre; Stat3flox/KO mice. In this case, a significant increase in the number of surviving motoneurons was found (79 ± 2%, n = 4, P < 0.01 versus untreated control), indicating that CNTF-mediated survival after axotomy does not solely rely on Stat3 signaling (Fig. 4).


Conditional gene ablation of Stat3 reveals differential signaling requirements for survival of motoneurons during development and after nerve injury in the adult.

Schweizer U, Gunnersen J, Karch C, Wiese S, Holtmann B, Takeda K, Akira S, Sendtner M - J. Cell Biol. (2002)

Beneficial effect of GDNF and CNTF on the survival of axotomized NF-L–Cre; Stat3flox/KO motoneurons. CNTF and GDNF rescued >50% of otherwise degenerated motoneurons, whereas the effect of BDNF was not significant. Motoneurons were counted in serial sections through the brain stem and statistical analysis was performed using ANOVA with Bonferroni's post hoc comparison. Single asterisk indicates P < 0.05; double asterisk indicates P < 0.01; triple asterisk indicates P < 0.001.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199226&req=5

fig4: Beneficial effect of GDNF and CNTF on the survival of axotomized NF-L–Cre; Stat3flox/KO motoneurons. CNTF and GDNF rescued >50% of otherwise degenerated motoneurons, whereas the effect of BDNF was not significant. Motoneurons were counted in serial sections through the brain stem and statistical analysis was performed using ANOVA with Bonferroni's post hoc comparison. Single asterisk indicates P < 0.05; double asterisk indicates P < 0.01; triple asterisk indicates P < 0.001.
Mentions: Transection of the facial nerve in newborn mice leads to degeneration of more than 80% of the corresponding motoneurons. These neurons can be rescued by local administration of neurotrophic factors (Sendtner et al., 1990, 1992; Henderson et al., 1994). To test whether this survival response is impaired in the absence of Stat3, GDNF and BDNF were locally administered to the lesioned facial nerve in 4-wk-old NF-L–Cre; Stat3flox/KO and NF-L–Cre; Stat3flox/wt mice. GDNF was most potent in NF-L–Cre; Stat3flox/KO animals and increased motoneuron survival to 86 ± 2% (n = 4, P < 0.01 compared with untreated control) at 2 wk after axotomy (Fig. 4) . BDNF application led to an increase in the number of surviving motoneurons from 57 ± 6% (n = 6) to 67 ± 6% (n = 5) that did not reach statistical significance (Fig. 4). We also applied CNTF to the proximal nerve stump in NF-L–Cre; Stat3flox/KO mice. In this case, a significant increase in the number of surviving motoneurons was found (79 ± 2%, n = 4, P < 0.01 versus untreated control), indicating that CNTF-mediated survival after axotomy does not solely rely on Stat3 signaling (Fig. 4).

Bottom Line: In contrast, motoneuron survival is significantly reduced after facial nerve lesion in the adult.Stat3 is essential for upregulation of Reg-2 and Bcl-xl expression in lesioned motoneurons.Our data show that Stat3 activation plays an essential role for motoneuron survival after nerve lesion in postnatal life but not during embryonic development, indicating that signaling requirements for motoneuron survival change during maturation.

View Article: PubMed Central - PubMed

Affiliation: Institute for Clinical Neurobiology, University of Würzburg, 97080 Würzburg, Germany.

ABSTRACT
Members of the ciliary neurotrophic factor (CNTF)/leukemia inhibitory factor (LIF)/cardiotrophin gene family are potent survival factors for embryonic and lesioned motoneurons. These factors act via receptor complexes involving gp130 and LIFR-beta and ligand binding leads to activation of various signaling pathways, including phosphorylation of Stat3. The role of Stat3 in neuronal survival was investigated in mice by Cre-mediated gene ablation in motoneurons. Cre is expressed under the neurofilament light chain (NF-L) promoter, starting around E12 when these neurons become dependent on neurotrophic support. Loss of motoneurons during the embryonic period of naturally occurring cell death is not enhanced in NF-L-Cre; Stat3(flox/KO) mice although motoneurons isolated from these mice need higher concentrations of CNTF for maximal survival in culture. In contrast, motoneuron survival is significantly reduced after facial nerve lesion in the adult. These neurons, however, can be rescued by the addition of neurotrophic factors, including CNTF. Stat3 is essential for upregulation of Reg-2 and Bcl-xl expression in lesioned motoneurons. Our data show that Stat3 activation plays an essential role for motoneuron survival after nerve lesion in postnatal life but not during embryonic development, indicating that signaling requirements for motoneuron survival change during maturation.

Show MeSH
Related in: MedlinePlus