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Genotype-specific effects of Mecp2 loss-of-function on morphology of Layer V pyramidal neurons in heterozygous female Rett syndrome model mice.

Rietveld L, Stuss DP, McPhee D, Delaney KR - Front Cell Neurosci (2015)

Bottom Line: Comparing basal dendrite morphology, soma and nuclear size of MeCP2+ to MeCP2- neurons reveals a significant cell autonomous, genotype specific effect of Mecp2.These data reveal cell autonomous effects of Mecp2 mutation on dendritic morphology, but also suggest non-cell autonomous effects with respect to cell size.Unexpectedly the MeCP2- neurons were smallest in brains where the XCI ratio was highly skewed toward MeCP2+, i.e., wild-type.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, University of Victoria Victoria, BC, Canada.

ABSTRACT
Rett syndrome (RTT) is a progressive neurological disorder primarily caused by mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2). The heterozygous female brain consists of mosaic of neurons containing both wild-type MeCP2 (MeCP2+) and mutant MeCP2 (MeCP2-). Three-dimensional morphological analysis was performed on individually genotyped layer V pyramidal neurons in the primary motor cortex of heterozygous (Mecp2(+/-) ) and wild-type (Mecp2(+/+) ) female mice ( > 6 mo.) from the Mecp2(tm1.1Jae) line. Comparing basal dendrite morphology, soma and nuclear size of MeCP2+ to MeCP2- neurons reveals a significant cell autonomous, genotype specific effect of Mecp2. MeCP2- neurons have 15% less total basal dendritic length, predominantly in the region 70-130 μm from the cell body and on average three fewer branch points, specifically loss in the second and third branch orders. Soma and nuclear areas of neurons of mice were analyzed across a range of ages (5-21 mo.) and X-chromosome inactivation (XCI) ratios (12-56%). On average, MeCP2- somata and nuclei were 15 and 13% smaller than MeCP2+ neurons respectively. In most respects branching morphology of neurons in wild-type brains (MeCP2 WT) was not distinguishable from MeCP2+ but somata and nuclei of MeCP2 WT neurons were larger than those of MeCP2+ neurons. These data reveal cell autonomous effects of Mecp2 mutation on dendritic morphology, but also suggest non-cell autonomous effects with respect to cell size. MeCP2+ and MeCP2- neuron sizes were not correlated with age, but were correlated with XCI ratio. Unexpectedly the MeCP2- neurons were smallest in brains where the XCI ratio was highly skewed toward MeCP2+, i.e., wild-type. This raises the possibility of cell non-autonomous effects that act through mechanisms other than globally secreted factors; perhaps competition for synaptic connections influences cell size and morphology in the genotypically mosaic brain of RTT model mice.

No MeSH data available.


Related in: MedlinePlus

MeCP2- neurons have a reduction in the number of total branch points and maximum branch order across Sholl radii. (A) Basal dendrites of all genotypes have similar path distances across Sholl radii. (B) All genotypes have the same number of primary dendrites. (C) MeCP2- neurons have an average of three fewer total branch points (a 17% reduction) compared to both other genotypes. The region between the dashed lines indicates where the MeCP2- neurons differ from MeCP2+ neurons in trend. (D) The maximum branch order reached by MeCP2- neurons at distances of 60 and 110 μm from the soma is lower than both other genotypes. ∗p < 0.05 and ∗∗p < 0.01.
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Figure 5: MeCP2- neurons have a reduction in the number of total branch points and maximum branch order across Sholl radii. (A) Basal dendrites of all genotypes have similar path distances across Sholl radii. (B) All genotypes have the same number of primary dendrites. (C) MeCP2- neurons have an average of three fewer total branch points (a 17% reduction) compared to both other genotypes. The region between the dashed lines indicates where the MeCP2- neurons differ from MeCP2+ neurons in trend. (D) The maximum branch order reached by MeCP2- neurons at distances of 60 and 110 μm from the soma is lower than both other genotypes. ∗p < 0.05 and ∗∗p < 0.01.

Mentions: Branch path distances at successive 10 μm Sholl radii were compared across genotypes (Figure 5A) to determine whether the cumulative length deficiency of MeCP2- neurons is due to a decreased tortuosity of the branches. No differences were found between the genotypes at any Sholl radii [two-way repeated measures ANOVA and Bonferroni post-tests, F(30,180) = 1.05, p = 0.4], indicating that the reduction in MeCP2- dendritic length is not due to straighter branches.


Genotype-specific effects of Mecp2 loss-of-function on morphology of Layer V pyramidal neurons in heterozygous female Rett syndrome model mice.

Rietveld L, Stuss DP, McPhee D, Delaney KR - Front Cell Neurosci (2015)

MeCP2- neurons have a reduction in the number of total branch points and maximum branch order across Sholl radii. (A) Basal dendrites of all genotypes have similar path distances across Sholl radii. (B) All genotypes have the same number of primary dendrites. (C) MeCP2- neurons have an average of three fewer total branch points (a 17% reduction) compared to both other genotypes. The region between the dashed lines indicates where the MeCP2- neurons differ from MeCP2+ neurons in trend. (D) The maximum branch order reached by MeCP2- neurons at distances of 60 and 110 μm from the soma is lower than both other genotypes. ∗p < 0.05 and ∗∗p < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4403522&req=5

Figure 5: MeCP2- neurons have a reduction in the number of total branch points and maximum branch order across Sholl radii. (A) Basal dendrites of all genotypes have similar path distances across Sholl radii. (B) All genotypes have the same number of primary dendrites. (C) MeCP2- neurons have an average of three fewer total branch points (a 17% reduction) compared to both other genotypes. The region between the dashed lines indicates where the MeCP2- neurons differ from MeCP2+ neurons in trend. (D) The maximum branch order reached by MeCP2- neurons at distances of 60 and 110 μm from the soma is lower than both other genotypes. ∗p < 0.05 and ∗∗p < 0.01.
Mentions: Branch path distances at successive 10 μm Sholl radii were compared across genotypes (Figure 5A) to determine whether the cumulative length deficiency of MeCP2- neurons is due to a decreased tortuosity of the branches. No differences were found between the genotypes at any Sholl radii [two-way repeated measures ANOVA and Bonferroni post-tests, F(30,180) = 1.05, p = 0.4], indicating that the reduction in MeCP2- dendritic length is not due to straighter branches.

Bottom Line: Comparing basal dendrite morphology, soma and nuclear size of MeCP2+ to MeCP2- neurons reveals a significant cell autonomous, genotype specific effect of Mecp2.These data reveal cell autonomous effects of Mecp2 mutation on dendritic morphology, but also suggest non-cell autonomous effects with respect to cell size.Unexpectedly the MeCP2- neurons were smallest in brains where the XCI ratio was highly skewed toward MeCP2+, i.e., wild-type.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, University of Victoria Victoria, BC, Canada.

ABSTRACT
Rett syndrome (RTT) is a progressive neurological disorder primarily caused by mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2). The heterozygous female brain consists of mosaic of neurons containing both wild-type MeCP2 (MeCP2+) and mutant MeCP2 (MeCP2-). Three-dimensional morphological analysis was performed on individually genotyped layer V pyramidal neurons in the primary motor cortex of heterozygous (Mecp2(+/-) ) and wild-type (Mecp2(+/+) ) female mice ( > 6 mo.) from the Mecp2(tm1.1Jae) line. Comparing basal dendrite morphology, soma and nuclear size of MeCP2+ to MeCP2- neurons reveals a significant cell autonomous, genotype specific effect of Mecp2. MeCP2- neurons have 15% less total basal dendritic length, predominantly in the region 70-130 μm from the cell body and on average three fewer branch points, specifically loss in the second and third branch orders. Soma and nuclear areas of neurons of mice were analyzed across a range of ages (5-21 mo.) and X-chromosome inactivation (XCI) ratios (12-56%). On average, MeCP2- somata and nuclei were 15 and 13% smaller than MeCP2+ neurons respectively. In most respects branching morphology of neurons in wild-type brains (MeCP2 WT) was not distinguishable from MeCP2+ but somata and nuclei of MeCP2 WT neurons were larger than those of MeCP2+ neurons. These data reveal cell autonomous effects of Mecp2 mutation on dendritic morphology, but also suggest non-cell autonomous effects with respect to cell size. MeCP2+ and MeCP2- neuron sizes were not correlated with age, but were correlated with XCI ratio. Unexpectedly the MeCP2- neurons were smallest in brains where the XCI ratio was highly skewed toward MeCP2+, i.e., wild-type. This raises the possibility of cell non-autonomous effects that act through mechanisms other than globally secreted factors; perhaps competition for synaptic connections influences cell size and morphology in the genotypically mosaic brain of RTT model mice.

No MeSH data available.


Related in: MedlinePlus