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Absence of Ret signaling in mice causes progressive and late degeneration of the nigrostriatal system.

Kramer ER, Aron L, Ramakers GM, Seitz S, Zhuang X, Beyer K, Smidt MP, Klein R - PLoS Biol. (2007)

Bottom Line: Support of ageing neurons by endogenous neurotrophic factors such as glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) may determine whether the neurons resist or succumb to neurodegeneration.We find that Ret, but not TrkB, ablation causes progressive and adult-onset loss of DA neurons specifically in the substantia nigra pars compacta, degeneration of DA nerve terminals in striatum, and pronounced glial activation.These findings establish Ret as a critical regulator of long-term maintenance of the nigrostriatal DA system and suggest conditional Ret mutants as useful tools for gaining insights into the molecular mechanisms involved in the development of PD.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Neurobiology, Max-Planck Institute of Neurobiology, Martinsried, Germany. ekramer@neuro.mpg.de

ABSTRACT
Support of ageing neurons by endogenous neurotrophic factors such as glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) may determine whether the neurons resist or succumb to neurodegeneration. GDNF has been tested in clinical trials for the treatment of Parkinson disease (PD), a common neurodegenerative disorder characterized by the loss of midbrain dopaminergic (DA) neurons. BDNF modulates nigrostriatal functions and rescues DA neurons in PD animal models. The physiological roles of GDNF and BDNF signaling in the adult nigrostriatal DA system are unknown. We generated mice with regionally selective ablations of the genes encoding the receptors for GDNF (Ret) and BDNF (TrkB). We find that Ret, but not TrkB, ablation causes progressive and adult-onset loss of DA neurons specifically in the substantia nigra pars compacta, degeneration of DA nerve terminals in striatum, and pronounced glial activation. These findings establish Ret as a critical regulator of long-term maintenance of the nigrostriatal DA system and suggest conditional Ret mutants as useful tools for gaining insights into the molecular mechanisms involved in the development of PD.

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Gliosis in Dorsal Striatum of DAT-Retlx/lx Mice(A, B, D, E, G, and H) Bright-field photomicrographs of dorsal striatum (A, B, D, and E) and SNpc (G and H) of 12-mo-old (A and B) and 24-mo-old (D, E, G, and H) control (A, D, and G) and DAT-Retlx/lx mutants (B, E, and H) stained for GFAP.(C, F, and I) Histograms showing the number of GFAP-positive reactive astrocytes (n = 3–5 per genotype). There is a 2-fold increase in the number of reactive astrocytes in the striatum of 2-y-old DAT-Retlx/lx mutants as compared to wild-type controls and DAT-TrkBlx/lx mutants (F) (p < 0.0001), whereas no difference is seen in 12-mo-old DAT-Retlx/lx mutants compared to controls (C) (p = 0.9). No significant increase in the number of reactive astrocytes is seen in the SNpc of 24-mo-old DAT-Retlx/lx mutants compared to controls (I) (p = 0.24). **, p < 0.01 (Student t-test). Scale bars indicate 50 μm.
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pbio-0050039-g005: Gliosis in Dorsal Striatum of DAT-Retlx/lx Mice(A, B, D, E, G, and H) Bright-field photomicrographs of dorsal striatum (A, B, D, and E) and SNpc (G and H) of 12-mo-old (A and B) and 24-mo-old (D, E, G, and H) control (A, D, and G) and DAT-Retlx/lx mutants (B, E, and H) stained for GFAP.(C, F, and I) Histograms showing the number of GFAP-positive reactive astrocytes (n = 3–5 per genotype). There is a 2-fold increase in the number of reactive astrocytes in the striatum of 2-y-old DAT-Retlx/lx mutants as compared to wild-type controls and DAT-TrkBlx/lx mutants (F) (p < 0.0001), whereas no difference is seen in 12-mo-old DAT-Retlx/lx mutants compared to controls (C) (p = 0.9). No significant increase in the number of reactive astrocytes is seen in the SNpc of 24-mo-old DAT-Retlx/lx mutants compared to controls (I) (p = 0.24). **, p < 0.01 (Student t-test). Scale bars indicate 50 μm.

Mentions: Having established substantial loss of nigrostriatal innervation and some striatal dysfunction in DAT-Retlx/lx mutants, we next asked if these degenerative processes would cause gliosis by invading reactive astrocytes. We used immunoreactivity against glial fibrillary acidic protein (GFAP) as an indicator of the astroglial response to genetically induced DA nerve terminal damage (Figure 5). Staining of 2-y-old brains revealed a massive reactive gliosis in dorsal striatum of DAT-Retlx/lx mutants compared to controls (Figure 5D–5F; n = 5 mice per group, p < 0.0001, Student t-test). No increased GFAP immunoreactivity was observed in 2-y-old DAT-TrkBlx/lx striatum (Figure 5F; n = 4 per group, p < 0.0001, Student t-test), or in younger (12-mo-old) DAT-Retlx/lx mutants (Figure 5A–5C; n = 3 mice per group, p = 0.90, Student t-test), or in other brain regions such as the neocortex of 2-y-old DAT-Retlx/lx mutants (unpublished data). GFAP immunoreactivity in SNpc of 2-y-old DAT-Retlx/lx mutants was not significantly enhanced compared to controls (Figure 5G–5I; n = 3 per group, p = 0.24, Student t-test) despite the marked loss of TH-positive cells in this structure. Because Ret is not genetically ablated in astrocytes, these results suggest that the gliosis in the striatum of DAT-Retlx/lx mice is non-cell autonomously caused by degenerating DA nerve terminals.


Absence of Ret signaling in mice causes progressive and late degeneration of the nigrostriatal system.

Kramer ER, Aron L, Ramakers GM, Seitz S, Zhuang X, Beyer K, Smidt MP, Klein R - PLoS Biol. (2007)

Gliosis in Dorsal Striatum of DAT-Retlx/lx Mice(A, B, D, E, G, and H) Bright-field photomicrographs of dorsal striatum (A, B, D, and E) and SNpc (G and H) of 12-mo-old (A and B) and 24-mo-old (D, E, G, and H) control (A, D, and G) and DAT-Retlx/lx mutants (B, E, and H) stained for GFAP.(C, F, and I) Histograms showing the number of GFAP-positive reactive astrocytes (n = 3–5 per genotype). There is a 2-fold increase in the number of reactive astrocytes in the striatum of 2-y-old DAT-Retlx/lx mutants as compared to wild-type controls and DAT-TrkBlx/lx mutants (F) (p < 0.0001), whereas no difference is seen in 12-mo-old DAT-Retlx/lx mutants compared to controls (C) (p = 0.9). No significant increase in the number of reactive astrocytes is seen in the SNpc of 24-mo-old DAT-Retlx/lx mutants compared to controls (I) (p = 0.24). **, p < 0.01 (Student t-test). Scale bars indicate 50 μm.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1808500&req=5

pbio-0050039-g005: Gliosis in Dorsal Striatum of DAT-Retlx/lx Mice(A, B, D, E, G, and H) Bright-field photomicrographs of dorsal striatum (A, B, D, and E) and SNpc (G and H) of 12-mo-old (A and B) and 24-mo-old (D, E, G, and H) control (A, D, and G) and DAT-Retlx/lx mutants (B, E, and H) stained for GFAP.(C, F, and I) Histograms showing the number of GFAP-positive reactive astrocytes (n = 3–5 per genotype). There is a 2-fold increase in the number of reactive astrocytes in the striatum of 2-y-old DAT-Retlx/lx mutants as compared to wild-type controls and DAT-TrkBlx/lx mutants (F) (p < 0.0001), whereas no difference is seen in 12-mo-old DAT-Retlx/lx mutants compared to controls (C) (p = 0.9). No significant increase in the number of reactive astrocytes is seen in the SNpc of 24-mo-old DAT-Retlx/lx mutants compared to controls (I) (p = 0.24). **, p < 0.01 (Student t-test). Scale bars indicate 50 μm.
Mentions: Having established substantial loss of nigrostriatal innervation and some striatal dysfunction in DAT-Retlx/lx mutants, we next asked if these degenerative processes would cause gliosis by invading reactive astrocytes. We used immunoreactivity against glial fibrillary acidic protein (GFAP) as an indicator of the astroglial response to genetically induced DA nerve terminal damage (Figure 5). Staining of 2-y-old brains revealed a massive reactive gliosis in dorsal striatum of DAT-Retlx/lx mutants compared to controls (Figure 5D–5F; n = 5 mice per group, p < 0.0001, Student t-test). No increased GFAP immunoreactivity was observed in 2-y-old DAT-TrkBlx/lx striatum (Figure 5F; n = 4 per group, p < 0.0001, Student t-test), or in younger (12-mo-old) DAT-Retlx/lx mutants (Figure 5A–5C; n = 3 mice per group, p = 0.90, Student t-test), or in other brain regions such as the neocortex of 2-y-old DAT-Retlx/lx mutants (unpublished data). GFAP immunoreactivity in SNpc of 2-y-old DAT-Retlx/lx mutants was not significantly enhanced compared to controls (Figure 5G–5I; n = 3 per group, p = 0.24, Student t-test) despite the marked loss of TH-positive cells in this structure. Because Ret is not genetically ablated in astrocytes, these results suggest that the gliosis in the striatum of DAT-Retlx/lx mice is non-cell autonomously caused by degenerating DA nerve terminals.

Bottom Line: Support of ageing neurons by endogenous neurotrophic factors such as glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) may determine whether the neurons resist or succumb to neurodegeneration.We find that Ret, but not TrkB, ablation causes progressive and adult-onset loss of DA neurons specifically in the substantia nigra pars compacta, degeneration of DA nerve terminals in striatum, and pronounced glial activation.These findings establish Ret as a critical regulator of long-term maintenance of the nigrostriatal DA system and suggest conditional Ret mutants as useful tools for gaining insights into the molecular mechanisms involved in the development of PD.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Neurobiology, Max-Planck Institute of Neurobiology, Martinsried, Germany. ekramer@neuro.mpg.de

ABSTRACT
Support of ageing neurons by endogenous neurotrophic factors such as glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) may determine whether the neurons resist or succumb to neurodegeneration. GDNF has been tested in clinical trials for the treatment of Parkinson disease (PD), a common neurodegenerative disorder characterized by the loss of midbrain dopaminergic (DA) neurons. BDNF modulates nigrostriatal functions and rescues DA neurons in PD animal models. The physiological roles of GDNF and BDNF signaling in the adult nigrostriatal DA system are unknown. We generated mice with regionally selective ablations of the genes encoding the receptors for GDNF (Ret) and BDNF (TrkB). We find that Ret, but not TrkB, ablation causes progressive and adult-onset loss of DA neurons specifically in the substantia nigra pars compacta, degeneration of DA nerve terminals in striatum, and pronounced glial activation. These findings establish Ret as a critical regulator of long-term maintenance of the nigrostriatal DA system and suggest conditional Ret mutants as useful tools for gaining insights into the molecular mechanisms involved in the development of PD.

Show MeSH
Related in: MedlinePlus