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 Mecp2tm1.1Jae 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.
Highlights
Rett Syndrome (RTT) is a postnatal neurological disorder that was first characterized by Rett (1966)
Sholl analysis (Sholl, 1953) was used to determine how a mutation in Mecp2 affects the dendritic morphology of MeCP2+ and MeCP2− neurons compared to MeCP2 WT neurons
MeCP2− Neurons have Reduced total Dendritic Length and Fewer Third and Fourth Order Branches We find that MeCP2− layer V pyramidal neurons in heterozygous brains have shorter basal dendritic length, due to their having fewer third and fourth order branches compared to MeCP2+ neurons
Summary
Rett Syndrome (RTT) is a postnatal neurological disorder that was first characterized by Rett (1966). It affects approximately one in 10,000 live female births (Laurvick et al, 2006). The majority of females with RTT are heterozygous for a mutation in the X-linked gene Methyl-CpGbinding Protein 2 (MECP2; Amir et al, 1999). Over 1000 mutations have been characterized along the entire length of the gene, including nonsense, missense, frameshift, and large truncation mutations (Amir and Zoghbi, 2000; Weaving et al, 2005; Philippe et al, 2006; Cuddapah et al, 2014), 65% of RTT cases are caused by eight common missense mutations in the region that encodes the methyl-CpG binding domain (MDB) of MeCP2 (MiltenbergerMiltenyi and Laccone, 2003)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
