The Tau-MeCP2 knockin mutation places the mouse MeCP2 cDNA sequence into exon 1 of the tau gene, in-frame with the endogenous tau start codon. Under control of the endogenous tau promoter/enhancer sequences, expression of the Tau-MeCP2 fusion protein (containing the first 31 amino acids of tau fused to the MeCP2 protein) is high in lung and kidney, low in heart, and very low in liver and spleen. Endogenous tau expression is abolished in the Tau-MeCP2 knockin allele. The axonal localization signal of tau is located in the 3' UTR, and therefore is not part of the Tau-MeCP2 mRNA. The onset of fusion protein expression correlates closely with endogenous tau expression (first detectable at 10.5 days post coitum [dpc]). While the amount of Mecp2 RNA is similar to Tau-MeCP2 RNA in heterozygous Tau-MeCP2 mice embryos and adult brain, the fusion protein expression level is approximately two-to-four times more abundant; suggesting a difference in either translation efficiency of the transcripts or protein stability. As such, the Tau-MeCP2 knockin results in MeCP2 overexpression directed primarily to heterochromatic foci of post-mitotic neurons in the brain. Heterozygous Tau-MeCP2 knockin mice tolerate ~2-3 fold MeCP2 overexpression levels in brain with no adverse effects on viability or fertility. By 3-5 months of age, heterozygotes display impaired motor coordination, heightened anxiety, and impaired learning and memory (accompanied by deficits in long-term potentiation and short-term synaptic plasticity). Mice homozygous for the Tau-MeCP2 knockin allele have ~4-6 fold MeCP2 overexpression levels in brain, resulting in a profound motor dysfunction with side-to-side swaying, tremors, and gait ataxia. Homozygotes are severely runted by weaning age (failure to thrive largely caused by inability to compete with littermates for food), remain smaller than wildtype mice, and fail to mate. The donating investigator (Dr. Lisa M. Monteggia) suggests using heterozygous mice for assessing behavioral traits, as the homozygous phenotype may complicate the analysis of behavioral testing.
