Overview

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.

Donating Investigator

Lisa M Monteggia, Univ of Texas Southwest Med Ctr Dallas

Genetic overview

Genetic Background	Generation

Mapt^{tm1(Mecp2)Jae}

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout, Inserted expressed sequence)	Mapt	microtubule-associated protein tau

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Research Applications

Neurobiology Research
Developmental Biology Research

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Base Price

Starting at:

$2,854.50 Domestic price Cryo Recovery

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Details

Detailed Description

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.

Development

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.

Expression Data

Expressed Gene	Mecp2, methyl CpG binding protein 2, mouse, laboratory
Site of Expression

Control Suggestions

Wild-type from the colony
000664 C57BL/6J

Additional Information

Considerations for Choosing Controls

Selected References

Luikenhuis S; Giacometti E; Beard CF; Jaenisch R. 2004. Expression of MeCP2 in postmitotic neurons rescues Rett syndrome in mice. Proc Natl Acad Sci U S A 101(16):6033-8PubMed: 15069197 MGI: J:89593
Na ES; Nelson ED; Adachi M; Autry AE; Mahgoub MA; Kavalali ET; Monteggia LM. 2012. A mouse model for MeCP2 duplication syndrome: MeCP2 overexpression impairs learning and memory and synaptic transmission. J Neurosci 32(9):3109-17PubMed: 22378884 MGI: J:182685

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Genetics

Mapt^{tm1(Mecp2)Jae}

Allele Symbol: Mapt^{tm1(Mecp2)Jae}

Allele Name	targeted mutation 1, Rudolf Jaenisch
Allele Type	Targeted (Null/Knockout, Inserted expressed sequence)
Allele Synonym(s)	Tau-Mecp2 ki
Gene Symbol and Name	Mapt, microtubule-associated protein tau
Gene Synonym(s)
Expressed Gene	Mecp2, methyl CpG binding protein 2, mouse, laboratory
Strain of Origin	(C57BL/6 x 129S4/SvJae)F1
Chromosome	11
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	Rudolf Jaenisch, Whitehead Institute, Massachusetts Institute of Technology

Disease/Phenotype

Disease Terms

Model with phenotypic similarity to human disease where etiologies are distinct. Human genes are associated with this disease. Orthologs of these genes do not appear in the mouse genotype(s).

syndromic X-linked intellectual disability Lubs type

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Neurobiology Research
- Neurodevelopmental Defects
  - Rett's syndrome
- Ataxia (Movement) Defects
- Behavioral and Learning Defects
  - high anxiety
- Neurodegeneration
- Tremor Defects
Developmental Biology Research
- Neurodevelopmental Defects

Mammalian Phenotype Terms by Genotype

The following phenotype information is associated with a similar, but not exact match to this JAX^® Mice strain

Genotype: Mapt^{tm1(Mecp2)Jae}/Mapt^{tm1(Mecp2)Jae}
involves: 129/Sv * C57BL/6

behavior/neurological phenotype

abnormal sexual interaction
- homozygotes do not mate

ataxia
- gait ataxia is seen in homozygous mutants

excessive scratching
- lesions are seen by 9 months probably as a result of excessive scratching

impaired balance
- homozygotes display side-to-side swaying

tremors

mammalian phenotype

mortality/aging
- Normal - no premature death is seen in homozygotes

vision/eye phenotype

cataract
- by 9 months homozygotes have developed cataracts

growth/size/body region phenotype

cachexia
- by 9 months homozygotes appear emaciated

postnatal growth retardation
- after weaning homozygotes remain smaller than wild-type littermates
- by weaning homozygotes are 60% smaller than wild-type littermates probably as a result of an inability to compete for food

integument phenotype

disheveled coat
- by 9 months homozygotes appear disheveled

Genotype: Mapt^{tm1(Mecp2)Jae}/Mapt⁺
involves: 129/Sv * C57BL/6

normal phenotype

no abnormal phenotype detected
- Normal - heterozygous mice are fertile and healthy with no obvious abnormalities

The following phenotype relates to a compound genotype created using this strain

Genotype: Mapt^{tm1(Mecp2)Jae}/Mapt^{tm1(Mecp2)Jae}
B6.Cg-Mapt

behavior/neurological phenotype

abnormal associative learning
- mutants display consistent freezing levels across all extinction trials, indicating impaired extinction learning

abnormal contextual conditioning behavior
- mutants exhibit an increase in freezing behavior in context (novel environment)-dependent fear conditioning 24 hours after training, suggesting enhanced associative learning

abnormal cued conditioning behavior
- however, mutants are incapable of extinguishing their conditioned response (freezing) to cue when cue is presented alone (without shock), indicating severe impairments in extinction learning and associative learning
- mutants do not show enhanced freezing behavior in the absence of a paired stimulus (baseline freezing) or before the tone in cued fear conditioning, suggesting that mutants learn to associate the cue with the shock
- mutants exhibit an increase in freezing behavior in cue (auditory tone)-dependent fear conditioning 24 hours after training, suggesting enhanced associative learning

abnormal object recognition memory
- in the NOR task to test ability to recognize a novel object, mutants spend less time with the novel object than wild-type mice and show less preference for the novel object over the familiar indicating impaired episodic memory

impaired coordination
- mutants spend less time on the rotarod than wild-type mice

increased anxiety-related response
- in the dark/light test, mutants spend less time in the light side and more time in the dark side, indicating heightened anxiety
- in the elevated plus maze, mutants spend less time in the center, more time in the closed arms, and less time in the open arms compared with wild-type

growth/size/body region phenotype

decreased body weight

nervous system phenotype

abnormal miniature excitatory postsynaptic currents
- hippocampal neurons exhibit enhanced miniature excitatory neurotransmission; hippocampal neurons show an increase in mEPSC frequency with no change in mEPSC amplitude

enhanced paired-pulse facilitation
- paired-pulse facilitation is augmented in mutants at the interstimulus intervals of 30 and 50 ms

reduced long term potentiation
- high frequency stimulation-induced long term potentiation is attenuated in hippocampal slices from mutants compared to wild-type mice

References

Luikenhuis S; Giacometti E; Beard CF; Jaenisch R. 2004. Expression of MeCP2 in postmitotic neurons rescues Rett syndrome in mice. Proc Natl Acad Sci U S A 101(16):6033-8PubMed: 15069197 MGI: J:89593
Na ES; Nelson ED; Adachi M; Autry AE; Mahgoub MA; Kavalali ET; Monteggia LM. 2012. A mouse model for MeCP2 duplication syndrome: MeCP2 overexpression impairs learning and memory and synaptic transmission. J Neurosci 32(9):3109-17PubMed: 22378884 MGI: J:182685

Additional - Mapt^{tm1(Mecp2)Jae} related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Separated PCR:Mapt
- Genotyping resources and troubleshooting
Breeding Considerations

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.
- Additional Breeding and Husbandry Support
Citation
When using the B6.Cg-Mapt^{tm1(Mecp2)Jae}/LimmJ mouse strain in a publication, please cite the originating article(s) and include JAX stock #018282 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Pricing & Availability

Cryo Recovery

Domestic
International

Live Mouse

Age

Genotype

Price

weeks

Cryorecovery - Pricing

Service/Product	Description	Price
	Heterozygous or wildtype for

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Frozen Mouse Embryo	B6.Cg-Mapt<tm1(Mecp2)Jae/LimmJ Frozen Embryo	$2595.00
Frozen Mouse Embryo	B6.Cg-Mapt<tm1(Mecp2)Jae/LimmJ Frozen Embryo	$2595.00
Frozen Mouse Embryo	B6.Cg-Mapt<tm1(Mecp2)Jae/LimmJ Frozen Embryo	$3373.50
Frozen Mouse Embryo	B6.Cg-Mapt<tm1(Mecp2)Jae/LimmJ Frozen Embryo	$3373.50

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Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Expression Data

Control Suggestions

Additional Information

Selected References

Mapttm1(Mecp2)Jae

Allele Symbol: Mapttm1(Mecp2)Jae

Disease Terms

Model with phenotypic similarity to human disease where etiologies are distinct. Human genes are associated with this disease. Orthologs of these genes do not appear in the mouse genotype(s).

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Mammalian Phenotype Terms by Genotype

Genotype: Mapttm1(Mecp2)Jae/Mapttm1(Mecp2)Jaeinvolves: 129/Sv * C57BL/6

behavior/neurological phenotype

mammalian phenotype

vision/eye phenotype

growth/size/body region phenotype

integument phenotype

Genotype: Mapttm1(Mecp2)Jae/Mapt+involves: 129/Sv * C57BL/6

normal phenotype

Genotype: Mapttm1(Mecp2)Jae/Mapttm1(Mecp2)JaeB6.Cg-Mapt

behavior/neurological phenotype

growth/size/body region phenotype

nervous system phenotype

References

Additional - Mapttm1(Mecp2)Jae related

Genotyping Protocols

Breeding Considerations

Citation

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Live Mouse

Cryorecovery - Pricing

Related Products and Services

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms Of Use

Additional Use Restrictions Apply

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Mapt^{tm1(Mecp2)Jae}

Allele Symbol: Mapt^{tm1(Mecp2)Jae}

Genotype: Mapt^{tm1(Mecp2)Jae}/Mapt^{tm1(Mecp2)Jae}
involves: 129/Sv * C57BL/6

Genotype: Mapt^{tm1(Mecp2)Jae}/Mapt⁺
involves: 129/Sv * C57BL/6

Genotype: Mapt^{tm1(Mecp2)Jae}/Mapt^{tm1(Mecp2)Jae}
B6.Cg-Mapt

Additional - Mapt^{tm1(Mecp2)Jae} related