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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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Inflammation in SNpc of DAT-Retlx/lx Mice(A, B, D–I, K, and L) Immunohistochemical stainings of dorsal striatum (A and B) and SNpc (D–I, K, and L) of 24-mo-old control (A, D, E, H, and K) and DAT-Retlx/lx mice (B, F, G, I, and L) for Iba-1 (A, B, E, G, H, and I), TH (D and F), and MAC1 (K and L). To localize microglial cells in SNpc, adjacent sections were stained for TH, and the area of the SNpc was marked and copied to the adjacent section stained for macrophages.(C, J, and M) Histograms showing the number of Iba-1–positive (C and J) and MAC1-positive (M) cells in the striatum (C) and SNpc (J and M) of 24-mo-old (C and J) DAT-Retlx/lx mice and controls. No significant alterations in the numbers of Iba-1–positive cells were observed in the striatum of 24-mo-old mutants and controls ([C] n = 4, p = 0.065). A significant increase in the numbers of Iba-1–positive cells was observed in the SNpc of 24-mo-old DAT-Retlx/lx mice compared to controls (J) (n = 5, p < 0.05). The same result was obtained using MAC1 as a second independent microglial marker (M) (n = 3, p < 0.05). *, p < 0.05 (Student t-test). Scale bars indicate 100 μm.
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pbio-0050039-g006: Inflammation in SNpc of DAT-Retlx/lx Mice(A, B, D–I, K, and L) Immunohistochemical stainings of dorsal striatum (A and B) and SNpc (D–I, K, and L) of 24-mo-old control (A, D, E, H, and K) and DAT-Retlx/lx mice (B, F, G, I, and L) for Iba-1 (A, B, E, G, H, and I), TH (D and F), and MAC1 (K and L). To localize microglial cells in SNpc, adjacent sections were stained for TH, and the area of the SNpc was marked and copied to the adjacent section stained for macrophages.(C, J, and M) Histograms showing the number of Iba-1–positive (C and J) and MAC1-positive (M) cells in the striatum (C) and SNpc (J and M) of 24-mo-old (C and J) DAT-Retlx/lx mice and controls. No significant alterations in the numbers of Iba-1–positive cells were observed in the striatum of 24-mo-old mutants and controls ([C] n = 4, p = 0.065). A significant increase in the numbers of Iba-1–positive cells was observed in the SNpc of 24-mo-old DAT-Retlx/lx mice compared to controls (J) (n = 5, p < 0.05). The same result was obtained using MAC1 as a second independent microglial marker (M) (n = 3, p < 0.05). *, p < 0.05 (Student t-test). Scale bars indicate 100 μm.

Mentions: Inflammatory processes are often associated with and activated by a variety of neuronal insults including PD and Alzheimer disease. We used immunohistochemistry for ionized binding calcium adapter molecule (Iba)-1 to detect microglia in brains of DAT-Retlx/lx mice. The numbers of Iba-1 immunopositive cells were not significantly increased in dorsal striatum of 2-y-old DAT-Retlx/lx mice compared to controls (Figure 6A–6C; n = 4 mice per group, p = 0.065, Student t-test). In contrast, we observed an approximately 45% increase in the number of Iba-1 immunopositive cells in SNpc of 2-y-old DAT-Retlx/lx mice compared to controls and DAT-TrkBlx/lx mice (Figure 6D–6J; n = 3 mice for DAT-TrkBlx/lx and n = 5 mice for controls and DAT-Retlx/lx, p < 0.05, Student t-test). Similar results were obtained using macrophage antigen alpha (MAC1, CD11b, or CR3) as a second, independent marker (Figure 6K–6M; n = 3 mice per group, p < 0.05, Student t-test). No differences in the numbers of Iba-1–positive microglial cells were detected in 1-y-old DAT-Retlx/lx mice compared to controls (unpublished data). Similar to reactive astrocytes, the Ret gene was not subjected to recombination in microglia of DAT-Retlx/lx mice, suggesting that the neuroinflammation occurred as a result of neuronal cell death.


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)

Inflammation in SNpc of DAT-Retlx/lx Mice(A, B, D–I, K, and L) Immunohistochemical stainings of dorsal striatum (A and B) and SNpc (D–I, K, and L) of 24-mo-old control (A, D, E, H, and K) and DAT-Retlx/lx mice (B, F, G, I, and L) for Iba-1 (A, B, E, G, H, and I), TH (D and F), and MAC1 (K and L). To localize microglial cells in SNpc, adjacent sections were stained for TH, and the area of the SNpc was marked and copied to the adjacent section stained for macrophages.(C, J, and M) Histograms showing the number of Iba-1–positive (C and J) and MAC1-positive (M) cells in the striatum (C) and SNpc (J and M) of 24-mo-old (C and J) DAT-Retlx/lx mice and controls. No significant alterations in the numbers of Iba-1–positive cells were observed in the striatum of 24-mo-old mutants and controls ([C] n = 4, p = 0.065). A significant increase in the numbers of Iba-1–positive cells was observed in the SNpc of 24-mo-old DAT-Retlx/lx mice compared to controls (J) (n = 5, p < 0.05). The same result was obtained using MAC1 as a second independent microglial marker (M) (n = 3, p < 0.05). *, p < 0.05 (Student t-test). Scale bars indicate 100 μm.
© Copyright Policy
Related In: Results  -  Collection

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

pbio-0050039-g006: Inflammation in SNpc of DAT-Retlx/lx Mice(A, B, D–I, K, and L) Immunohistochemical stainings of dorsal striatum (A and B) and SNpc (D–I, K, and L) of 24-mo-old control (A, D, E, H, and K) and DAT-Retlx/lx mice (B, F, G, I, and L) for Iba-1 (A, B, E, G, H, and I), TH (D and F), and MAC1 (K and L). To localize microglial cells in SNpc, adjacent sections were stained for TH, and the area of the SNpc was marked and copied to the adjacent section stained for macrophages.(C, J, and M) Histograms showing the number of Iba-1–positive (C and J) and MAC1-positive (M) cells in the striatum (C) and SNpc (J and M) of 24-mo-old (C and J) DAT-Retlx/lx mice and controls. No significant alterations in the numbers of Iba-1–positive cells were observed in the striatum of 24-mo-old mutants and controls ([C] n = 4, p = 0.065). A significant increase in the numbers of Iba-1–positive cells was observed in the SNpc of 24-mo-old DAT-Retlx/lx mice compared to controls (J) (n = 5, p < 0.05). The same result was obtained using MAC1 as a second independent microglial marker (M) (n = 3, p < 0.05). *, p < 0.05 (Student t-test). Scale bars indicate 100 μm.
Mentions: Inflammatory processes are often associated with and activated by a variety of neuronal insults including PD and Alzheimer disease. We used immunohistochemistry for ionized binding calcium adapter molecule (Iba)-1 to detect microglia in brains of DAT-Retlx/lx mice. The numbers of Iba-1 immunopositive cells were not significantly increased in dorsal striatum of 2-y-old DAT-Retlx/lx mice compared to controls (Figure 6A–6C; n = 4 mice per group, p = 0.065, Student t-test). In contrast, we observed an approximately 45% increase in the number of Iba-1 immunopositive cells in SNpc of 2-y-old DAT-Retlx/lx mice compared to controls and DAT-TrkBlx/lx mice (Figure 6D–6J; n = 3 mice for DAT-TrkBlx/lx and n = 5 mice for controls and DAT-Retlx/lx, p < 0.05, Student t-test). Similar results were obtained using macrophage antigen alpha (MAC1, CD11b, or CR3) as a second, independent marker (Figure 6K–6M; n = 3 mice per group, p < 0.05, Student t-test). No differences in the numbers of Iba-1–positive microglial cells were detected in 1-y-old DAT-Retlx/lx mice compared to controls (unpublished data). Similar to reactive astrocytes, the Ret gene was not subjected to recombination in microglia of DAT-Retlx/lx mice, suggesting that the neuroinflammation occurred as a result of neuronal cell death.

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