Human Molecular Genetics Advance Access originally published online on July 17, 2007
Human Molecular Genetics 2007 16(19):2315-2325; doi:10.1093/hmg/ddm185
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Cell-specific expression of wild-type MeCP2 in mouse models of Rett syndrome yields insight about pathogenesis
1 Centro de Estudios Científicos, Valdivia 5110246, Chile, 2 Universidad Austral de Chile, Valdivia 905-9100, Chile, 3 Howard Hughes Medical Institute, Chevy Chase, MD, USA, 4 Department of Molecular and Human Genetics and 5 Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA
* To whom correspondence should be addressed. Tel: +56 63234569; Fax: +56 63234517; Email: jyoung{at}cecs.cl
Received May 7, 2007; Accepted July 8, 2007
Rett syndrome (RTT), a leading cause of mental retardation with autistic features in females, is caused by mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2). RTT is characterized by a diverse set of neurological features that includes cognitive, motor, behavioral and autonomic disturbances. The diverse features suggest that specific neurons contribute to particular phenotypes and raise the question whether restoring MeCP2 function in a cell-specific manner will rescue some of the phenotypes seen in RTT. To address this, we generated transgenic mice expressing inducible MeCP2 under the control of the brain-specific promoters calcium/calmodulin-dependent protein kinase II (CamKII) or neuron-specific enolase (Eno2) and bred them onto mouse models lacking functional MeCP2. Expression of normal MeCP2 in either CamKII or Eno2 distribution was unable to prevent the appearance of most of the phenotypes of the RTT mouse models. These results suggest that most RTT phenotypes are caused either by disruption of complex neural networks involving neurons throughout the brain or by disruption of the function of specific neurons outside of the broad CamKII or Eno2 distribution.
The authors wish it to be known that, in their opinion, the first 2 authors should be regarded as joint First Authors.
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