Hum Mol Genet. 2004 Mar 15.
Multiple pathways regulate MeCP2 expression in normal brain development and exhibit defects in autism-spectrum disorders.
Samaco RC, Nagarajan RP, Braunschweig D, LaSalle JM.
Medical Microbiology and Immunology, Rowe Program in Human Genetics, School of Medicine, University of California, Davis, USA.
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Abstract: Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in MECP2, encoding methyl-CpG-binding protein 2 (MeCP2). Although MECP2 is ubiquitously transcribed, MeCP2 expression is developmentally regulated and heterogeneous in neuronal subpopulations, defined as MeCP2(lo) and MeCP2(hi). To test the hypothesis that pathways affecting MeCP2 expression changes may be defective in RTT, autism and other neurodevelopmental disorders without MECP2 mutations, a high-throughput quantitation of MeCP2 expression was performed on a tissue microarray containing frontal cortex samples from 28 different patients with neurodevelopmental disorders and age-matched controls. Combined quantitative analyses of MeCP2 protein and alternatively polyadenylated transcript levels were performed by laser scanning cytometry and tested for significant differences from age-matched controls. Normal cerebral samples showed an increase in total MeCP2 expression and the percentage of MeCP2(hi) cells with age that could be explained by increased MECP2 transcription within the MeCP2(hi) population. A significant decrease in the relative usage of the long transcript in the MeCP2(lo) population was observed in postnatal compared to fetal brain, but alternate polyadenylation did not correlate with MeCP2 expression changes at the single cell level. Brain samples from several related neurodevelopmental disorders, including autism, pervasive developmental disorder, Prader-Willi and Angelman syndromes showed significant differences in MeCP2 expression from age-matched controls by apparently different transcriptional and post-transcriptional mechanisms. These results suggest that multiple pathways regulate the complex developmental expression of MeCP2 and are defective in autism-spectrum disorders in addition to RTT.

My abstract

Rett syndrome is a neurodevelopmental disorder that presents with cognitive impairment and autistic behavior and is caused by mutations in the MECP2 gene (on chromosome X) which carries the instructions for making methyl-CpG-binding protein 2 (MeCP2). The MeCP2 protein, which is found throughout both fetal and adult brains, has two different forms - a short form which contains a 1.9 kb transcript from the MECP2 grene and a long form which contains a 10 kb-long transcript that includes the 1.9 kb coding region of MECP2 as well as an exceptionally long untranslated region. To further complicate things, some brain neurons have relatively high levels of the MeCP2 protein and are called MeCP2(hi) neurons, while other neurons have relatively low levels of MeCP2 and are called MeCP2(lo) neurons.

MeCP2 expression is developmentally regulated, that is, there are changes in the total amount of MeCP2 protein in the brain according to age, as well as changes in the amounts of short and long transcript forms of MeCP2 and changes in the number of MeCP2(lo) and MeCP2(hi) neurons. During normal brain development, the total amount of MeCP2 increases and there is a progressive increase in the number of MeCP2(hi) neurons from infancy to adulthood. At the same time, the amount of long-transcript MeCP2 falls relative to the amount of short-transcript MeCP2, even though juvenile and adult MeCP2(hi) neurons have more long-transcript MeCP2 than juvenile and adult MeCP2(lo) neurons.

In PWS, there are significantly higher MeCP2 levels in the MeCP2(hi) neurons compared to control subjects, even though total MECP2 levels are significantly lower. In addition, there are higher levels of both short and long-transcript MECP2 proteins in PWS. In other words, PWS brains do not shift to more MeCP2(hi) neurons during growth, nor does the normal fall in the amount of long-transcript MeCP2 occur. That means that the loss of expression of the genetic information on the paternal chromosome 15 gene that occurs in PWS somehow affects the expression of the MECP2 gene on chromosome X.