Expression of MeCP2 in postmitotic neurons rescues Rett syndrome in mice.
Mutations in MECP2 are the cause of Rett syndrome (RTT) in humans, a neurodevelopmental disorder that affects mainly girls. MeCP2 is a protein that binds CpG dinucleotides and is thought to act as a global transcriptional repressor. It is highly expressed in neurons, but not in glia, of the postnatal brain. The timing of MeCP2 activation correlates with the maturation of the central nervous system, and recent reports suggest that MeCP2 may be involved in the formation of synaptic contacts and may function in activity-dependent neuronal gene expression. Deletion or targeted mutation of Mecp2 in mice leads to a Rett-like phenotype. Selective mutation of Mecp2 in postnatal neurons leads to a similar, although delayed, phenotype, suggesting that MeCP2 plays a role in postmitotic neurons. Here we test the hypothesis that the symptoms of RTT are exclusively caused by a neuronal MeCP2 deficiency by placing Mecp2 expression under the control of a neuron-specific promoter. Expression of the Mecp2 transgene in postmitotic neurons resulted in symptoms of severe motor dysfunction. Transgene expression in Mecp2 mutant mice, however, rescued the RTT phenotype.
Luikenhuis
Sandra
S
Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, USA.
Giacometti
Emanuela
E
Beard
Caroline F
CF
Jaenisch
Rudolf
R
D000818:Animals; D001483:Base Sequence; D002868:Chromosomal Proteins, Non-Histone; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D007150:Immunohistochemistry; D008297:Male; D051783:Methyl-CpG-Binding Protein 2; D051379:Mice; D008822:Mice, Transgenic; D008938:Mitosis; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D012097:Repressor Proteins; D015518:Rett Syndrome / Q000235:genetics*; D016875:tau Proteins / Q000235:genetics
D002868:Chromosomal Proteins, Non-Histone; D017931:DNA Primers; D004268:DNA-Binding Proteins; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D012097:Repressor Proteins; D016875:tau Proteins