Limits...
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 fewer third and fourth order branches compared to both other genotypes. (A) Branch order diagram depicting the increasing order values with each successive branch point from the cell body. Symmetrical and asymmetrical branching patterns are shown (calculated at the second order branch points) which result in partition asymmetry values of 0 and 1, respectively. (B) MeCP2- neurons have fewer second and third order branch points compared to both genotypes. (C) Branching patterns in MeCP2- neurons are unaltered. (D) MeCP2- neurons have fewer third and fourth order branches. (E) MeCP2- neurons have reduced dendritic length in the third and fourth branch orders. (F) The average length of MeCP2- branches per branch order does not differ from that of MeCP2+ branches. ∗p < 0.05, ∗∗p < 0.01 and ∗∗∗p < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4403522&req=5

Figure 6: MeCP2- neurons have fewer third and fourth order branches compared to both other genotypes. (A) Branch order diagram depicting the increasing order values with each successive branch point from the cell body. Symmetrical and asymmetrical branching patterns are shown (calculated at the second order branch points) which result in partition asymmetry values of 0 and 1, respectively. (B) MeCP2- neurons have fewer second and third order branch points compared to both genotypes. (C) Branching patterns in MeCP2- neurons are unaltered. (D) MeCP2- neurons have fewer third and fourth order branches. (E) MeCP2- neurons have reduced dendritic length in the third and fourth branch orders. (F) The average length of MeCP2- branches per branch order does not differ from that of MeCP2+ branches. ∗p < 0.05, ∗∗p < 0.01 and ∗∗∗p < 0.001.

Mentions: Total dendritic length of MeCP2- neurons is reduced. (A) MeCP- neurons have decreased dendritic length at distances of 70–130 μm from the soma compared to both MeCP2 WT and MeCP2+ neurons. The region between the dashed lines indicates where the slopes of MeCP2- and MeCP2+ cells deviate. (B) MeCP2- neuron total basal dendritic length is 15% less (275 μm) compared to both MeCP2 WT and MeCP2+ neurons. Dashed lines indicate the average maximum radial distance reached for each genotype. No significant difference was found between the genotypes in this measure. ∗p < 0.05, ∗∗p < 0.01, and ∗∗∗p < 0.001. For Figures 4–6, 82 MeCP2 WT neurons, 98 MeCP2+ and 59 MeCP2- neurons were filled and reconstructed (five animals per genotype, 16–31 cells per animal).


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 fewer third and fourth order branches compared to both other genotypes. (A) Branch order diagram depicting the increasing order values with each successive branch point from the cell body. Symmetrical and asymmetrical branching patterns are shown (calculated at the second order branch points) which result in partition asymmetry values of 0 and 1, respectively. (B) MeCP2- neurons have fewer second and third order branch points compared to both genotypes. (C) Branching patterns in MeCP2- neurons are unaltered. (D) MeCP2- neurons have fewer third and fourth order branches. (E) MeCP2- neurons have reduced dendritic length in the third and fourth branch orders. (F) The average length of MeCP2- branches per branch order does not differ from that of MeCP2+ branches. ∗p < 0.05, ∗∗p < 0.01 and ∗∗∗p < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: MeCP2- neurons have fewer third and fourth order branches compared to both other genotypes. (A) Branch order diagram depicting the increasing order values with each successive branch point from the cell body. Symmetrical and asymmetrical branching patterns are shown (calculated at the second order branch points) which result in partition asymmetry values of 0 and 1, respectively. (B) MeCP2- neurons have fewer second and third order branch points compared to both genotypes. (C) Branching patterns in MeCP2- neurons are unaltered. (D) MeCP2- neurons have fewer third and fourth order branches. (E) MeCP2- neurons have reduced dendritic length in the third and fourth branch orders. (F) The average length of MeCP2- branches per branch order does not differ from that of MeCP2+ branches. ∗p < 0.05, ∗∗p < 0.01 and ∗∗∗p < 0.001.
Mentions: Total dendritic length of MeCP2- neurons is reduced. (A) MeCP- neurons have decreased dendritic length at distances of 70–130 μm from the soma compared to both MeCP2 WT and MeCP2+ neurons. The region between the dashed lines indicates where the slopes of MeCP2- and MeCP2+ cells deviate. (B) MeCP2- neuron total basal dendritic length is 15% less (275 μm) compared to both MeCP2 WT and MeCP2+ neurons. Dashed lines indicate the average maximum radial distance reached for each genotype. No significant difference was found between the genotypes in this measure. ∗p < 0.05, ∗∗p < 0.01, and ∗∗∗p < 0.001. For Figures 4–6, 82 MeCP2 WT neurons, 98 MeCP2+ and 59 MeCP2- neurons were filled and reconstructed (five animals per genotype, 16–31 cells per animal).

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