The Tau-MeCP2 knockin allele replaces endogenous microtubule-associated protein tau gene expression with Tau-MeCP2 fusion protein expression. Homozygous Tau-MeCP2 knockin mice recapitulate many key phenotypes of MECP2 duplication syndrome in humans. They may also be used for neuron-specific MeCP2 expression to rescue the Rett syndrome phenotype of other MeCP2 mutant mice.
Lisa M Monteggia, Univ of Texas Southwest Med Ctr DallasRead More +
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.
The pTAU-MeCP2pAneo targeting vector was designed by Dr. Rudolf Jaenisch (Whitehead Institute MIT) to insert the mouse methyl CpG binding protein 2 (Mecp2) coding sequence, an SV40 late polyadenylation signal, and a PGK-neomycin resistance cassette as an in-frame fusion into exon 1 of the microtubule-associated protein tau locus (Mapt). The 1455 nucleotide MeCP2 cDNA sequence was obtained via PCR amplification of IMAGE clone 1395411 isolated from a C57BL/6 male mouse (GenBank accession no. AI181668). The targeting vector was electroporated into (C57BL/6 x 129S4/SvJae)F1-derived V6.5 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient (DBA/2 x C57BL/6)F1 blastocysts. Chimeric males were bred with C57BL/6 females to generate the Tau-MeCP2 knockin colony. Heterozygous (Tau-MeCP2 ki/+) mice were backcrossed with C57BL/6J mice more than ten generations. In 2006, Dr. Jaenisch sent black heterozygous females to Dr. Lisa M. Monteggia (The University of Texas Southwestern Medical Center). There, the colony was maintained by breeding heterozygous females with wildtype sibling males and/or with C57BL/6J males for several generations. In 2012, Dr. Monteggia sent heterozygous males to The Jackson Laboratory Repository. Upon arrival, mice were bred to C57BL/6J inbred mice (Stock No. 000664) for at least one generation to establish The Jackson Laboratory Repository colony.
|Expressed Gene||Mecp2, methyl CpG binding protein 2, mouse, laboratory|
|Site of Expression|
|Allele Name||targeted mutation 1, Rudolf Jaenisch|
|Allele Type||Targeted (Inserted expressed sequence, Null/Knockout)|
|Allele Synonym(s)||Tau-Mecp2 ki|
|Gene Symbol and Name||Mapt, microtubule-associated protein tau|
|Gene Synonym(s)||AI413597; AW045860; DDPAC; FTDP-17; MAPTL; MSTD; MTBT1; MTBT2; Mtapt; Mtapt; PPND; PPP1R103; RNPTAU; TAU; Tau; Tau; expressed sequence AI413597; expressed sequence AW045860; pTau|
|Expressed Gene||Mecp2, methyl CpG binding protein 2, mouse, laboratory|
|Strain of Origin||(C57BL/6 x 129S4/SvJae)F1|
|Molecular Note||The mouse Mecp2 coding sequence, a modified Kozak sequence and a neo-cassette were placed in-frame into exon 1 of Mapt via homologous combination. The resulting fusion protein contained the first 31 amino acids of Mapt fused to Mecp2 and was highly expressed in the brain (in post-mitotic neurons), lung, and kidney.|
|Mutations Made By|| |
Dr. Rudolf Jaenisch, Whitehead Institute (MIT)
When maintaining a live colony, heterozygous mice may be bred with wildtype mice from the colony or with C57BL/6J inbred mice. Homozygous mice exhibit profound motor, learning, and behavioral abnormalities, and the donating investigator reports that homozygous mice do not mate.
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