eNews April 03, 2012

Rett syndrome research at The Jackson Laboratory

At The Jackson Laboratory, we are committed to help find a treatment or cure for Rett syndrome. Our Rett syndrome mouse models are genetically stable, well characterized and critical tools in that endeavor. This article showcases some of the most promising of these mouse models and directs you to a few real-life stories of people who are working with our scientists to develop new models.

Rett syndrome

Rett syndrome is an autism spectrum disorder that almost exclusively affects girls, usually before they are two years old. Affected girls develop normally for the first 6-18 months but then lose speech and motor skills and may develop autistic behaviors, cognitive deficits, stereotyped hand movements (hand wringing), ataxia (abnormal gait), seizures, slow head growth (microcephaly) and cardiac and respiratory problems. Women with Rett syndrome can live well into adulthood; palliative care is key to their well-being.

The MECP2 gene and X-inactivation

Virtually all girls with Rett syndrome have a spontaneous mutation in the methyl-CpG binding protein 2 (MECP2) gene on the X chromosome. More than 200 mutations in eight different "hot spots" within the MECP2 locus have been associated with the disease. MECP2 is a widespread transcriptional regulator that binds to methylated DNA and blocks transcription. It is most concentrated in neurons of the brain and is highly expressed in the central nervous system during neuronal maturation. It may be involved in the alternative splicing of proteins critical for normal communication between nerve cells.

Although girls are born with two X chromosomes (one paternal and one maternal), in early embryonic development, in a process known as X-inactivation, one X chromosome is permanently inactivated. (Only one is needed to direct the production of enough MECP2 for cells to function normally.) Whether the chromosome with or without the mutant MECP2 allele is inactivated varies randomly from cell to cell. As a result, Rett syndrome ranges from mild to severe: the higher the percentage of cells whose active X chromosome has the mutant MECP2 allele, the more severe the disease.

JAX® Mice strains for researching Rett syndrome

We distribute numerous Rett syndrome mouse models, including the following:

STOCK Mecp2tm3.1Bird/J (014610) was designed by Adrian Bird, Ph.D., at the University of Edinburgh to study mosaic MECP2 expression in living neurons. It contains an Mecp2-EGFP fusion transgene (Mecp2tm3.1Bird), an enhanced green fluorescent protein (EGFP) sequence and a loxP-flanked neomycin resistance sequence-STOP cassette inserted in the 3' untranslated region of the Mecp2 gene. Because the EGFP is downstream of Mecp2, this mouse expresses Mecp2 normally and is phenotypically normal. It expresses EGFP throughout the brain but predominantly in mature neurons. When it is bred to an Mecp2-deficient strain, it produces offspring in which mosaic neuronal Mecp2 expression can be tracked by visually tracking EGFP expression. It may be used to study X-inactivation and its reactivation by candidate therapies, epigenetic deregulation, neurodevelopmental disorders, neuronal maturation, brain function and synaptogenesis.

B6.129P2(C)-Mecp2tm1.1Bird/J (003890) is a constitutive Mecp2 knockout that exhibits Rett syndrome-like neurological defects.

B6.129P2-Mecp2tm2Bird/J (006849) contains a loxP-flanked STOP cassette downstream of Mecp2 exon 1 and exhibits Rett syndrome-like neurological defects. When bred to a strain that expresses Cre recombinase in neurons, it produces offspring in which the floxed STOP cassette is deleted, Mecp2 expression is normal and Rett syndrome-like neurological defects are reversed.

B6.129P2-Mecp2tm1Bird/J (007177) has two functional loxP sites flanking exons 3-4 of the Mecp2 gene. When bred to a strain that expresses Cre recombinase in neurons, e.g., B6.Cg-Tg(Nes-cre)1Kln/J (003771), it produces offspring in which exons 3-4 are deleted in Cre-expressing tissue and which develop Rett syndrome-like neurological defects. When bred to a strain that expresses Cre recombinase in GABAergic neurons, e.g., B6.FVB-Tg(Slc32a1-cre)2.1Hzo/FrkJ (017535), it produces offspring that exhibit Rett syndrome and autism spectrum disorder-like defects.

STOCK Mecp2tm1.1Irsf/J (012602) contains the amino acid mutation R255X in exon 4 of the Mecp2 gene, analogous to an MECP2 mutation found in humans with Rett syndrome. Females may develop normally or may exhibit a mild phenotype, including some obesity, reduced coordination and lethargy; males develop severe neurological defects.