B6.129P2(C)-Mecp2^tm1.1Bird/J

Stock number: 003890
Product name: Mecp2^-
Research areas: Mouse/Human Gene Homologs, Neurobiology Research

Description

This Mecp2 knockout strain is a mouse model of human Rett Syndrome. Mecp2-deficient males (Mecp2^-/Y) exhibit mobility problems and a range of Rett Syndrome-like characteristics at 3-8 weeks of age. Heterozygous females exhibit a much later onset (~6 months of age).

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Detailed description

The Mecp2 knockout mutation is X-linked; therefore the Mecp2-deficient mice are Mecp2^-/- (homozygous) females and Mecp2^-/Y (hemizygous) males.
Mecp2 null mice are viable and appear normal at birth. No Mecp2 gene product (mRNA or protein) is detected in tissues. Mobility problems are apparent at 3-8 weeks of age. Mice exhibit hindlimb clasping and uneven breathing. An uneven wearing of teeth associated with misalignment of the jaws is observed in 50% of the animals. Adult males do not mate and their testes remain internal although sperm are present in the cauda epididymis. Symptom progression is variable, but mice can be expected to undergo weight loss, shivering, continued mobility problems before succumbing. Expected lifespan is approximately 50-60 days.
Heterozygous female mice display mobility problems and hindlimb clasping starting at about 6 months, but the symptoms are reported not to be progressive.
This Mecp2 knockout strain is useful for studying Rett Syndrome.

The Jackson Laboratory maintains this strain by breeding females heterozygous for the X-linked Mecp2 knockout mutation with C57BL/6J males. It has been our experience that less than 1% of all offspring genotype as "homozygous" females (120 of 36,437 females; July 2020). A cohort of "homozygous" females examined for karyotype were found to be XO. In general, the "homozygous" females present much the same as hemizygous males, with obesity, hind limb clasping, gradual decline in hind limb mobility and death between 50-100 days of age. In addition, rare instances of obese heterozygous females have also been noted in the colony, which could possibly represent the same phenomenon. When identified in our colony, "homozygous" females are removed and the breeding unit that produced it is discontinued. Furthermore, heterozygous females commonly exhibit seizures which are sometimes fatal.

Importation of this model was supported in part by the Rett Syndrome Research Foundation.

Development

A targeting vector was designed to insert loxP sites around exons 3 and 4 of the methyl CpG binding protein 2 gene (Mecp2) on the X chromosome. The construct was transfected into 129P2/OlaHsd-derived E14TG2a embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6 blastocysts. Chimeric offspring were bred to C57BL/6 mice to produce heterozygous floxed females. The floxed line was bred to homozygosity and maintained in this form. Homozygous floxed female mice were crossed with male CMV-Cre mice (BALB/c background) in which the Cre gene is located on the X chromosome and is ubiquitously expressed. The resulting female mice, heterozygous for the germline recombined null allele, were mated with wild type C57BL/6 animals. Each subsequent generation of heterozygous females have been mated to inbred C57BL/6 males to maintain the line.

Allele

Symbol: Mecp2^tm1.1Bird
Name: targeted mutation 1.1, Adrian Bird
MGI accession ID: MGI:2137311
Generation method: Targeted
Attributes: Null/Knockout
Marker symbol: Mecp2
Marker name: methyl CpG binding protein 2
Chromosome: X
Strain of origin: 129P2/OlaHsd
Molecular note: Insertion of a neomycin resistance cassette into the Mecp2 gene introduced loxP sites that flank exons 3 and 4, and added an intron and polyadenylation signal from the human beta globin gene. A CMV-Cre mediated recombination event in the germline then removed exons 3 and 4. Northern blot analysis did not detect Mecp2 mRNA in tissues of mutant male mice (-/y), nor did Western blot analysis detect protein in these tissues.