JAX Notes July 01, 2002

A Cre-conditional mouse model for Rett Syndrome

The congenital disorder Rett syndrome is one of the most common causes of mental retardation in women, occurring in 1:10,000 to 1:15,000 female births (Armstrong, 1997). Affected females develop normally for the first 6-18 months after birth. Subsequently, they lose the capacity for voluntary movements, including speech and hand skills. In addition, affected individuals often develop stereotyped, repetitive hand motions and an abnormal gait and may suffer from seizures.

Earlier studies indicated that mutations in the X-linked gene methyl CpG binding protein 2 (MECP2) are responsible for the phenotypes associated with Rett syndrome (Ellaway and Christadoulou, 1999). MECP2 binds to methylated DNA, and is believed to play a role in silencing gene expression, but the specific mechanisms through which mutations in MECP2 result in the disease remain unknown.

Initial efforts to generate Mecp2-null mutant mice were unsuccessful, presumably due to a requirement for MECP2 in mouse embryogenesis. Recently, however, Adrian Bird’s group at the University of Edinburgh have used Cre-lox technology to overcome the requirement for MeCP2 in embryogenesis and have produced a viable Mecp2-null mouse (Guy, Hendrich, Holmes, Martin, and Bird 2001). These mice, B6.129P2(C)-Mecp2tm1.1Bird (Stock Number 003890), are available at The Jackson Laboratory and are a useful model in the study of Rett syndrome.

Homozygous Mecp2tm1.1Bird mice are viable and appear normal at birth. No Mecp2 gene product (mRNA or protein) is detected in tissues. Mobility problems become apparent at 3-8 weeks of age, and 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 caudal epididymis. Symptom progression is variable, but mice can be expected to undergo weight loss, shivering and mobility problems before succumbing. Expected lifespan is about 50-60 days. Heterozygous female mice display mobility problems and hind limb clasping starting at about 6 months, but the symptoms appear not to be progressive.

Importation of this model to The Jackson Laboratory was supported, in part, by the Rett Syndrome Research Foundation.

References

1 Armstrong, DD. Review of Rett syndrome. J. Neuropath Exp Neurol 1997; 56:843-849.

2 Ellaway, C, Christadoulou, J. Rett syndrome:  Clinical update and review of recent genetic advances. J Paediatr Child Health 1999; 35:419-426.

3 Guy J, Hendrich B, Holmes M, Martin JE, Bird A. A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome. Nat Genet 2001; 27:332-336.