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Rgs6 is required for adult maintenance of dopaminergic neurons in the ventral substantia nigra.

Bifsha P, Yang J, Fisher RA, Drouin J - PLoS Genet. (2014)

Bottom Line: Unilateral cell loss is accompanied by contralateral degenerating neurons that exhibit smaller cell size, altered morphology and reduced dendritic network.The degenerating neurons have low levels of tyrosine hydroxylase (TH) and decreased nuclear Pitx3; accordingly, expression of many Pitx3 target gene products is altered, including Vmat2, Bdnf, Aldh1a1 (Adh2) and Fgf10.Rgs6-dependent protection is thus critical for adult survival and maintenance of the vSNc mDA neurons that are most affected in PD.

View Article: PubMed Central - PubMed

Affiliation: Laboratoire de Génétique Moléculaire, Institut de Recherches Cliniques de Montréal (IRCM) Montréal, Quebec, Canada; Division of Experimental Medicine, McGill University, Montréal, Quebec, Canada.

ABSTRACT
Parkinson disease (PD) is characterized by the preferential, but poorly understood, vulnerability to degeneration of midbrain dopaminergic (mDA) neurons in the ventral substantia nigra compacta (vSNc). These sensitive mDA neurons express Pitx3, a transcription factor that is critical for their survival during development. We used this dependence to identify, by flow cytometry and expression profiling, the negative regulator of G-protein signaling Rgs6 for its restricted expression in these neurons. In contrast to Pitx3-/- mDA neurons that die during fetal (vSNc) or post-natal (VTA) period, the vSNc mDA neurons of Rgs6-/- mutant mice begin to exhibit unilateral signs of degeneration at around 6 months of age, and by one year cell loss is observed in a fraction of mice. Unilateral cell loss is accompanied by contralateral degenerating neurons that exhibit smaller cell size, altered morphology and reduced dendritic network. The degenerating neurons have low levels of tyrosine hydroxylase (TH) and decreased nuclear Pitx3; accordingly, expression of many Pitx3 target gene products is altered, including Vmat2, Bdnf, Aldh1a1 (Adh2) and Fgf10. These low TH neurons also express markers of increased dopamine signaling, namely increased DAT and phospho-Erk1/2 expression. The late onset degeneration may reflect the protective action of Rgs6 against excessive DA signaling throughout life. Rgs6-dependent protection is thus critical for adult survival and maintenance of the vSNc mDA neurons that are most affected in PD.

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Unilateral loss of Pitx3-positive dopaminergic neurons in ventral SNc of Rgs6−/− mice.(A) Immunoperoxidase staining for TH on representative coronal midbrain sections showing less SNc TH+ neurons on one side of Rgs6−/− mice at 1 year of age compared to sib control. Sections are identified with Bregma position. Scale bar 400 µm. (B) Number of TH+ cells in SNc and VTA of TH-stained coronal sections across midbrain (every 30 µm). Cell counts are represented as means +/− S.D. (***p<0.005). (C) Nissl staining of vSNc sections contiguous to A shows fewer cell bodies and abnormal elongated neurons in Rgs6−/− mice compared to control. Scale bar 100 µm. (D) Double immunofluorescence staining for TH (green) and Pitx3 (red) on sections contiguous to A showing a marked loss of TH+Pitx3+ cells in Rgs6−/− mice. Scale bar 100 µm.
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pgen-1004863-g004: Unilateral loss of Pitx3-positive dopaminergic neurons in ventral SNc of Rgs6−/− mice.(A) Immunoperoxidase staining for TH on representative coronal midbrain sections showing less SNc TH+ neurons on one side of Rgs6−/− mice at 1 year of age compared to sib control. Sections are identified with Bregma position. Scale bar 400 µm. (B) Number of TH+ cells in SNc and VTA of TH-stained coronal sections across midbrain (every 30 µm). Cell counts are represented as means +/− S.D. (***p<0.005). (C) Nissl staining of vSNc sections contiguous to A shows fewer cell bodies and abnormal elongated neurons in Rgs6−/− mice compared to control. Scale bar 100 µm. (D) Double immunofluorescence staining for TH (green) and Pitx3 (red) on sections contiguous to A showing a marked loss of TH+Pitx3+ cells in Rgs6−/− mice. Scale bar 100 µm.

Mentions: The first phenotype was a partial loss of SNc TH-positive cells on one side of the brain (random unilateral) (Fig. 4A and Figure S1). Quantification of TH-positive cells in SNc and VTA indicated a loss of about 35±6% (SD) in the SNc of the affected side (Fig. 4B). The loss of TH-positive cells was further supported by fewer Nissl-positive cells in SNc of Rgs6−/− mice (Fig. 4C). In addition, the Nissl stain revealed the presence of cells with abnormal elongated morphology that were found unilaterally within the SNc (Fig. 4C). The loss of TH-positive cells is correlated with a loss of Pitx3-positive cells (Fig. 4D).


Rgs6 is required for adult maintenance of dopaminergic neurons in the ventral substantia nigra.

Bifsha P, Yang J, Fisher RA, Drouin J - PLoS Genet. (2014)

Unilateral loss of Pitx3-positive dopaminergic neurons in ventral SNc of Rgs6−/− mice.(A) Immunoperoxidase staining for TH on representative coronal midbrain sections showing less SNc TH+ neurons on one side of Rgs6−/− mice at 1 year of age compared to sib control. Sections are identified with Bregma position. Scale bar 400 µm. (B) Number of TH+ cells in SNc and VTA of TH-stained coronal sections across midbrain (every 30 µm). Cell counts are represented as means +/− S.D. (***p<0.005). (C) Nissl staining of vSNc sections contiguous to A shows fewer cell bodies and abnormal elongated neurons in Rgs6−/− mice compared to control. Scale bar 100 µm. (D) Double immunofluorescence staining for TH (green) and Pitx3 (red) on sections contiguous to A showing a marked loss of TH+Pitx3+ cells in Rgs6−/− mice. Scale bar 100 µm.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4263397&req=5

pgen-1004863-g004: Unilateral loss of Pitx3-positive dopaminergic neurons in ventral SNc of Rgs6−/− mice.(A) Immunoperoxidase staining for TH on representative coronal midbrain sections showing less SNc TH+ neurons on one side of Rgs6−/− mice at 1 year of age compared to sib control. Sections are identified with Bregma position. Scale bar 400 µm. (B) Number of TH+ cells in SNc and VTA of TH-stained coronal sections across midbrain (every 30 µm). Cell counts are represented as means +/− S.D. (***p<0.005). (C) Nissl staining of vSNc sections contiguous to A shows fewer cell bodies and abnormal elongated neurons in Rgs6−/− mice compared to control. Scale bar 100 µm. (D) Double immunofluorescence staining for TH (green) and Pitx3 (red) on sections contiguous to A showing a marked loss of TH+Pitx3+ cells in Rgs6−/− mice. Scale bar 100 µm.
Mentions: The first phenotype was a partial loss of SNc TH-positive cells on one side of the brain (random unilateral) (Fig. 4A and Figure S1). Quantification of TH-positive cells in SNc and VTA indicated a loss of about 35±6% (SD) in the SNc of the affected side (Fig. 4B). The loss of TH-positive cells was further supported by fewer Nissl-positive cells in SNc of Rgs6−/− mice (Fig. 4C). In addition, the Nissl stain revealed the presence of cells with abnormal elongated morphology that were found unilaterally within the SNc (Fig. 4C). The loss of TH-positive cells is correlated with a loss of Pitx3-positive cells (Fig. 4D).

Bottom Line: Unilateral cell loss is accompanied by contralateral degenerating neurons that exhibit smaller cell size, altered morphology and reduced dendritic network.The degenerating neurons have low levels of tyrosine hydroxylase (TH) and decreased nuclear Pitx3; accordingly, expression of many Pitx3 target gene products is altered, including Vmat2, Bdnf, Aldh1a1 (Adh2) and Fgf10.Rgs6-dependent protection is thus critical for adult survival and maintenance of the vSNc mDA neurons that are most affected in PD.

View Article: PubMed Central - PubMed

Affiliation: Laboratoire de Génétique Moléculaire, Institut de Recherches Cliniques de Montréal (IRCM) Montréal, Quebec, Canada; Division of Experimental Medicine, McGill University, Montréal, Quebec, Canada.

ABSTRACT
Parkinson disease (PD) is characterized by the preferential, but poorly understood, vulnerability to degeneration of midbrain dopaminergic (mDA) neurons in the ventral substantia nigra compacta (vSNc). These sensitive mDA neurons express Pitx3, a transcription factor that is critical for their survival during development. We used this dependence to identify, by flow cytometry and expression profiling, the negative regulator of G-protein signaling Rgs6 for its restricted expression in these neurons. In contrast to Pitx3-/- mDA neurons that die during fetal (vSNc) or post-natal (VTA) period, the vSNc mDA neurons of Rgs6-/- mutant mice begin to exhibit unilateral signs of degeneration at around 6 months of age, and by one year cell loss is observed in a fraction of mice. Unilateral cell loss is accompanied by contralateral degenerating neurons that exhibit smaller cell size, altered morphology and reduced dendritic network. The degenerating neurons have low levels of tyrosine hydroxylase (TH) and decreased nuclear Pitx3; accordingly, expression of many Pitx3 target gene products is altered, including Vmat2, Bdnf, Aldh1a1 (Adh2) and Fgf10. These low TH neurons also express markers of increased dopamine signaling, namely increased DAT and phospho-Erk1/2 expression. The late onset degeneration may reflect the protective action of Rgs6 against excessive DA signaling throughout life. Rgs6-dependent protection is thus critical for adult survival and maintenance of the vSNc mDA neurons that are most affected in PD.

Show MeSH
Related in: MedlinePlus