» Articles » PMID: 25941473

Genotype-specific Effects of Mecp2 Loss-of-function on Morphology of Layer V Pyramidal Neurons in Heterozygous Female Rett Syndrome Model Mice

Overview
Specialty Cell Biology
Date 2015 May 6
PMID 25941473
Citations 24
Authors
Affiliations
Soon will be listed here.
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.

Citing Articles

Acute MeCP2 loss in adult mice reveals transcriptional and chromatin changes that precede neurological dysfunction and inform pathogenesis.

Bajikar S, Zhou J, OHara R, Tirumala H, Durham M, Trostle A Neuron. 2024; 113(3):380-395.e8.

PMID: 39689710 PMC: 11802321. DOI: 10.1016/j.neuron.2024.11.006.


Mice lacking acid-sensing ion channel 2 in the medial prefrontal cortex exhibit social dominance.

Lin B, Jin Z, Park G, Ge Q, Singh K, Ryan V W Sci Adv. 2024; 10(43):eadn7573.

PMID: 39453995 PMC: 11506137. DOI: 10.1126/sciadv.adn7573.


A small-molecule TrkB ligand improves dendritic spine phenotypes and atypical behaviors in female Rett syndrome mice.

Medeiros D, Ayala-Baylon K, Egido-Betancourt H, Miller E, Chapleau C, Robinson H Dis Model Mech. 2024; 17(6).

PMID: 38785269 PMC: 11139040. DOI: 10.1242/dmm.050612.


Transition from Animal-Based to Human Induced Pluripotent Stem Cells (iPSCs)-Based Models of Neurodevelopmental Disorders: Opportunities and Challenges.

Guerreiro S, Maciel P Cells. 2023; 12(4).

PMID: 36831205 PMC: 9954744. DOI: 10.3390/cells12040538.


Autism Spectrum Disorder: Neurodevelopmental Risk Factors, Biological Mechanism, and Precision Therapy.

Wang L, Wang B, Wu C, Wang J, Sun M Int J Mol Sci. 2023; 24(3).

PMID: 36768153 PMC: 9915249. DOI: 10.3390/ijms24031819.


References
1.
Chapleau C, Calfa G, Lane M, Albertson A, Larimore J, Kudo S . Dendritic spine pathologies in hippocampal pyramidal neurons from Rett syndrome brain and after expression of Rett-associated MECP2 mutations. Neurobiol Dis. 2009; 35(2):219-33. PMC: 2722110. DOI: 10.1016/j.nbd.2009.05.001. View

2.
Guy J, Cheval H, Selfridge J, Bird A . The role of MeCP2 in the brain. Annu Rev Cell Dev Biol. 2011; 27:631-52. DOI: 10.1146/annurev-cellbio-092910-154121. View

3.
McGraw C, Samaco R, Zoghbi H . Adult neural function requires MeCP2. Science. 2011; 333(6039):186. PMC: 3150190. DOI: 10.1126/science.1206593. View

4.
Sirianni N, Naidu S, Pereira J, Pillotto R, Hoffman E . Rett syndrome: confirmation of X-linked dominant inheritance, and localization of the gene to Xq28. Am J Hum Genet. 1998; 63(5):1552-8. PMC: 1377565. DOI: 10.1086/302105. View

5.
Puck J, Willard H . X inactivation in females with X-linked disease. N Engl J Med. 1998; 338(5):325-8. DOI: 10.1056/NEJM199801293380611. View