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The relative contribution of proximal 5' flanking sequence and microsatellite variation on brain vasopressin 1a receptor (Avpr1a) gene expression and behavior.

Donaldson ZR, Young LJ - PLoS Genet. (2013)

Bottom Line: Previous work has suggested that both the proximal 5' flanking region and a polymorphic microsatellite element within that region of the vole Avpr1a gene are associated with variation in V1a receptor (V1aR) distribution and behavior, but neither has been causally linked.This is the first direct evidence that polymorphic microsatellite elements near behaviorally relevant genes can contribute to diversity in brain gene expression profiles, providing a mechanism for generating behavioral diversity both at the individual and species level.However, our results suggest that many features of species-specific expression patterns are mediated by elements outside of the immediate 5' flanking region of the gene.

View Article: PubMed Central - PubMed

Affiliation: Division of Integrative Neuroscience, Department of Psychiatry, Columbia University, New York, New York, United States of America. zoe.donaldson@gmail.com

ABSTRACT
Certain genes exhibit notable diversity in their expression patterns both within and between species. One such gene is the vasopressin receptor 1a gene (Avpr1a), which exhibits striking differences in neural expression patterns that are responsible for mediating differences in vasopressin-mediated social behaviors. The genomic mechanisms that contribute to these remarkable differences in expression are not well understood. Previous work has suggested that both the proximal 5' flanking region and a polymorphic microsatellite element within that region of the vole Avpr1a gene are associated with variation in V1a receptor (V1aR) distribution and behavior, but neither has been causally linked. Using homologous recombination in mice, we reveal the modest contribution of proximal 5' flanking sequences to species differences in V1aR distribution, and confirm that variation in V1aR distribution impacts stress-coping in the forced swim test. We also demonstrate that the vole Avpr1a microsatellite structure contributes to Avpr1a expression in the amygdala, thalamus, and hippocampus, mirroring a subset of the inter- and intra-species differences observed in central V1aR patterns in voles. This is the first direct evidence that polymorphic microsatellite elements near behaviorally relevant genes can contribute to diversity in brain gene expression profiles, providing a mechanism for generating behavioral diversity both at the individual and species level. However, our results suggest that many features of species-specific expression patterns are mediated by elements outside of the immediate 5' flanking region of the gene.

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Microsatellite differences modulate species differences in V1aR patterns.Mice carrying the prairie vole Avpr1a microsatellite (B), as compared to mice carrying the meadow microsatellite (D), have higher V1aR binding in the dentate gyrus (DG), paraventricular nucleus of the thalamus (PVThal), and the central amygdala (CeA). These differences mirror those observed in the same brain regions of prairie (A) and meadow voles (C). (E) shows the difference in V1a levels relative to WT mice. Data are represented as mean ± SEM; n = 7–8 animals/group; **p<0.001, #p<0.05 compared to WT.
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pgen-1003729-g004: Microsatellite differences modulate species differences in V1aR patterns.Mice carrying the prairie vole Avpr1a microsatellite (B), as compared to mice carrying the meadow microsatellite (D), have higher V1aR binding in the dentate gyrus (DG), paraventricular nucleus of the thalamus (PVThal), and the central amygdala (CeA). These differences mirror those observed in the same brain regions of prairie (A) and meadow voles (C). (E) shows the difference in V1a levels relative to WT mice. Data are represented as mean ± SEM; n = 7–8 animals/group; **p<0.001, #p<0.05 compared to WT.

Mentions: Having established that replacement of the 5′ flanking region contributes to differences in V1aR levels in the thalamus, amygdala, ventral pallidum, and hippocampus, we next investigated whether differences in the composition of the Avpr1a microsatellite might mediate species differences in V1aR binding within any of these regions. Specifically we compared V1aR binding in KI mice homozygous for either the prairie long (pvKI-long) or meadow vole (mvKI) Avpr1a microsatellite, and identified a significant effect of both brain region (F(4, 77) = 114.7, p<0.001) and genotype (F(4, 77) = 160.9, p<0.001) on V1aR levels. In addition, there was a significant interaction between brain region and genotype (F(4, 77) = 74.2, p<0.001), and simple main effects with Sidak-adjusted α showed that pvKI-long animals had significantly higher levels of V1aR than mvKI animals in the CeA (p<0.001), PVThal (p = 0.002), and DG (p<0.001), but not in the lateral septum (LS; p = 0.68; Figure 4E) or ventral pallidum (VP; p = 0.75; Figure 4E).


The relative contribution of proximal 5' flanking sequence and microsatellite variation on brain vasopressin 1a receptor (Avpr1a) gene expression and behavior.

Donaldson ZR, Young LJ - PLoS Genet. (2013)

Microsatellite differences modulate species differences in V1aR patterns.Mice carrying the prairie vole Avpr1a microsatellite (B), as compared to mice carrying the meadow microsatellite (D), have higher V1aR binding in the dentate gyrus (DG), paraventricular nucleus of the thalamus (PVThal), and the central amygdala (CeA). These differences mirror those observed in the same brain regions of prairie (A) and meadow voles (C). (E) shows the difference in V1a levels relative to WT mice. Data are represented as mean ± SEM; n = 7–8 animals/group; **p<0.001, #p<0.05 compared to WT.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3757045&req=5

pgen-1003729-g004: Microsatellite differences modulate species differences in V1aR patterns.Mice carrying the prairie vole Avpr1a microsatellite (B), as compared to mice carrying the meadow microsatellite (D), have higher V1aR binding in the dentate gyrus (DG), paraventricular nucleus of the thalamus (PVThal), and the central amygdala (CeA). These differences mirror those observed in the same brain regions of prairie (A) and meadow voles (C). (E) shows the difference in V1a levels relative to WT mice. Data are represented as mean ± SEM; n = 7–8 animals/group; **p<0.001, #p<0.05 compared to WT.
Mentions: Having established that replacement of the 5′ flanking region contributes to differences in V1aR levels in the thalamus, amygdala, ventral pallidum, and hippocampus, we next investigated whether differences in the composition of the Avpr1a microsatellite might mediate species differences in V1aR binding within any of these regions. Specifically we compared V1aR binding in KI mice homozygous for either the prairie long (pvKI-long) or meadow vole (mvKI) Avpr1a microsatellite, and identified a significant effect of both brain region (F(4, 77) = 114.7, p<0.001) and genotype (F(4, 77) = 160.9, p<0.001) on V1aR levels. In addition, there was a significant interaction between brain region and genotype (F(4, 77) = 74.2, p<0.001), and simple main effects with Sidak-adjusted α showed that pvKI-long animals had significantly higher levels of V1aR than mvKI animals in the CeA (p<0.001), PVThal (p = 0.002), and DG (p<0.001), but not in the lateral septum (LS; p = 0.68; Figure 4E) or ventral pallidum (VP; p = 0.75; Figure 4E).

Bottom Line: Previous work has suggested that both the proximal 5' flanking region and a polymorphic microsatellite element within that region of the vole Avpr1a gene are associated with variation in V1a receptor (V1aR) distribution and behavior, but neither has been causally linked.This is the first direct evidence that polymorphic microsatellite elements near behaviorally relevant genes can contribute to diversity in brain gene expression profiles, providing a mechanism for generating behavioral diversity both at the individual and species level.However, our results suggest that many features of species-specific expression patterns are mediated by elements outside of the immediate 5' flanking region of the gene.

View Article: PubMed Central - PubMed

Affiliation: Division of Integrative Neuroscience, Department of Psychiatry, Columbia University, New York, New York, United States of America. zoe.donaldson@gmail.com

ABSTRACT
Certain genes exhibit notable diversity in their expression patterns both within and between species. One such gene is the vasopressin receptor 1a gene (Avpr1a), which exhibits striking differences in neural expression patterns that are responsible for mediating differences in vasopressin-mediated social behaviors. The genomic mechanisms that contribute to these remarkable differences in expression are not well understood. Previous work has suggested that both the proximal 5' flanking region and a polymorphic microsatellite element within that region of the vole Avpr1a gene are associated with variation in V1a receptor (V1aR) distribution and behavior, but neither has been causally linked. Using homologous recombination in mice, we reveal the modest contribution of proximal 5' flanking sequences to species differences in V1aR distribution, and confirm that variation in V1aR distribution impacts stress-coping in the forced swim test. We also demonstrate that the vole Avpr1a microsatellite structure contributes to Avpr1a expression in the amygdala, thalamus, and hippocampus, mirroring a subset of the inter- and intra-species differences observed in central V1aR patterns in voles. This is the first direct evidence that polymorphic microsatellite elements near behaviorally relevant genes can contribute to diversity in brain gene expression profiles, providing a mechanism for generating behavioral diversity both at the individual and species level. However, our results suggest that many features of species-specific expression patterns are mediated by elements outside of the immediate 5' flanking region of the gene.

Show MeSH
Related in: MedlinePlus