NeuroanatomyTemporal shift in methyl-CpG binding protein 2 expression in a mouse model of Rett syndrome
Section snippets
Experimental procedures
Mecp2tm1.1Bird mice (Jackson Laboratory, Bar Harbor, ME, USA) on a C57BL/6 background (heterozygote backcrossed with C57BL/6 males for at least nine generations) were used for all experimental procedures. The Johns Hopkins University Institutional Animal Care and Use Committee approved all animal protocols, and guidelines from the U.S. National Institutes of Health Guide for the Care and Use of Laboratory Animals were followed. All efforts were made to minimize the number of animals used and
MeCP2 immunostaining in the cortex of younger adult WT and HET mice differs in pattern and in neuronal number
MeCP2 immunostaining in younger adult (7–9 week old) WT controls exhibited distinct laminar boundaries (Figs. 2a and 3a–b). Adjacent sections labeled with the neuronal marker, NeuN had a very similar staining pattern (Fig. 2b). This similar pattern indicated that the anti-MeCP2 and anti-NeuN antibodies labeled the same neuronal populations in WT mice, as has previously been shown (Akbarian et al 2001, Shahbazian et al 2002b, Jung et al 2003, Mullaney et al 2004). Interestingly, the NeuN
Discussion
In this study we investigated the differences between younger (7–9 week old) and older (24–95 week old) adult WT, HET, and MECP2-null mice. We found morphological and corresponding numerical differences in the percentage of cells expressing MeCP2. Furthermore, in analyzing the two developmental stages, we found that the percentage of cortical neurons expressing MeCP2 increased from younger to older adult ages in HET animals.
The use of unbiased stereologic procedures allowed us to investigate
Acknowledgments
This work was supported by NICHD grants HD24448 and HD24061. We thank Ms. Pingping Zhang and Ms. Brandy McKinney for technical assistance and Dr. SakkuBai Naidu and Dr. Walter Kaufmann for their helpful suggestions on the manuscript.
References (57)
- et al.
Expression pattern of the Rett syndrome gene MeCP2 in primate prefrontal cortex
Neurobiol Dis
(2001) - et al.
Polymorphic X-chromosome inactivation of the human TIMP1 gene
Am J Hum Genet
(1999) - et al.
Use of frozen sections to determine neuronal number in the murine hippocampus and neocortex using the optical disector and optical fractionator
Brain Res Brain Res Protoc
(2004) - et al.
Expression of genes from the human active and inactive X chromosomes
Am J Hum Genet
(1997) - et al.
Gene expression profiling in postmortem Rett syndrome braindifferential gene expression and patient classification
Neurobiol Dis
(2001) Escape from X inactivation in human and mouse
Trends Genet
(1995)- et al.
Clonality and X-inactivation patterns in hematopoietic cell populations detected by the highly informative M27 beta DNA probe
Blood
(1994) Recent advances in X-chromosome inactivation
Curr Opin Cell Biol
(2004)- et al.
The role of different X-inactivation pattern on the variable clinical phenotype with Rett syndrome
Brain Dev
(2001) - et al.
Directed migration of neuronal precursors into the ischemic cerebral cortex and striatum
Mol Cell Neurosci
(2003)
Neurobiology of Rett syndromea genetic disorder of synapse development
Brain Dev
Purification, sequence, and cellular localization of a novel chromosomal protein that binds to methylated DNA
Cell
Developmental expression of methyl-CpG binding protein 2 is dynamically regulated in the rodent brain
Neuroscience
Skewed X-chromosome inactivation is a common feature of X-linked mental retardation disorders
Am J Hum Genet
Mice with truncated MeCP2 recapitulate many Rett syndrome features and display hyperacetylation of histone H3
Neuron
The role of X-chromosome inactivation in the manifestation of Rett syndrome
Brain Dev
Mutations in the gene encoding methyl-CpG-binding protein 2 cause Rett syndrome
Brain Dev
Rett syndrome and beyondrecurrent spontaneous and familial MECP2 mutations at CpG hotspots
Am J Hum Genet
New stereological methods for counting neurons
Neurobiol Aging
X-chromosome inactivation patterns are unbalanced and affect the phenotypic outcome in a mouse model of Rett syndrome
Am J Hum Genet
The X-linked methylated DNA binding protein, Mecp2, is subject to X inactivation in the mouse
Mamm Genome
Influence of mutation type and X chromosome inactivation on Rett syndrome phenotypes
Ann Neurol
Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl- CpG-binding protein 2
Nat Genet
Elevated methyl-CpG-binding protein 2 expression is acquired during postnatal human brain development and is correlated with alternative polyadenylation
J Mol Med
X-chromosome inactivation ratios affect wild-type MeCP2 expression within mosaic Rett syndrome and Mecp2-/+ mouse brain
Hum Mol Genet
Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice
Nat Genet
Xce haplotypes show modified methylation in a region of the active X chromosome lying 3′ to Xist
Proc Natl Acad Sci U S A
Isolation, physical mapping, and northern analysis of the X-linked human gene encoding methyl CpG-binding protein, MECP2
Mamm Genome
Cited by (27)
Altered trajectories of neurodevelopment and behavior in mouse models of Rett syndrome
2019, Neurobiology of Learning and MemoryCitation Excerpt :The percentage of all cells (neurons + glia) expressing MeCP2 + in Mecp2-heterozygous mice ranged from 28 to 35% compared to a 51–63% range for WT mice; the differences were significant at 7, 14 and 20+ weeks of age (Supplemental Table 3, Fig. 3C). The results were different than those from our previous analysis (Metcalf, Mullaney, Johnston, & Blue, 2006). We believe the differences in the studies may be due to the less variability in MeCP2 immunostaining and in neuronal staining with MBA2 compared to NeuN immunostaining.
Are dopamine receptor and transporter changes in Rett syndrome reflected in Mecp2-deficient mice?
2018, Experimental NeurologyNeuronal morphology in MeCP2 mouse models is intrinsically variable and depends on age, cell type, and Mecp2 mutation
2013, Neurobiology of DiseaseCitation Excerpt :While reduced dendritic complexity, soma size, and spine density are commonly identified in Mecp2 mutant mice (Belichenko et al., 2009a,b; Fukuda et al., 2005; Kishi and Macklis, 2004; Robinson et al., 2012; Stuss et al., 2012; Tropea et al., 2009), these structural phenotypes also differ by cellular subtype and developmental time point (Chapleau et al., 2012; Fukuda et al., 2005). The extent to which these factors influence cellular structure, however, is not well understood, as the use of different techniques and Mecp2 mouse models have made direct comparisons across studies difficult (Belichenko et al., 2008, 2009a; Chapleau et al., 2009; Cohen et al., 2011; Fukuda et al., 2005; Jentarra et al., 2010; Kishi and Macklis, 2004; Metcalf et al., 2006; Moretti et al., 2006; Robinson et al., 2012; Stuss et al., 2012; Zhou et al., 2006). For example, reduced spine density has been reported in motor cortex layer II/III and V pyramidal neurons in 3-week-old Mecp2-null mice (Belichenko et al., 2009a,b), and in layer V at 8 weeks (Tropea et al., 2009), while no change in spine density has been reported in the somatosensory cortex layer II/III pyramidal neurons in 8-week-old Mecp2-null mice (Kishi and Macklis, 2004).