Description

Strain Information

Type Congenic; Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Additional information on Congenic nomenclature. Mating System Wild-type x Heterozygote         (Female x Male)   26-OCT-12 Mating System Heterozygote x Wild-type         (Female x Male)   26-OCT-12 Species laboratory mouse   Donating Investigator Lisa M Monteggia,   Univ of Texas Southwest Med Ctr Dallas

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.

Control Information

	Control
	Wild-type from the colony
	000664 C57BL/6J
Considerations for Choosing Controls

Related Strains

Strains carrying other alleles of Mapt

007251	B6.129-Mapttm1Hnd/J
005491	B6.Cg-Mapttm1(EGFP)Klt Tg(MAPT)8cPdav/J
012639	B6;129S4-Mapttm3(HDAC2)Jae/J
004808	STOCK Mapttm1(EGFP)Klt Tg(MAPT)8cPdav/J
004779	STOCK Mapttm1(EGFP)Klt/J

View Strains carrying other alleles of Mapt     (5 strains)

Strains carrying other alleles of Mecp2

003890	B6.129P2(C)-Mecp2tm1.1Bird/J
007177	B6.129P2-Mecp2tm1Bird/J
006849	B6.129P2-Mecp2tm2Bird/J
005439	B6.129S-Mecp2tm1Hzo/J
006847	B6;129P2-Mecp2tm1Bird/J
017741	B6N.129(Cg)-Mecp2tm1.1Joez/J
016207	B6N.129-Mecp2tm1.1Vnar/J
012602	STOCK Mecp2tm1.1Irsf/J
014610	STOCK Mecp2tm3.1Bird/J

View Strains carrying other alleles of Mecp2     (9 strains)

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI

- 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).

Lubs X-Linked Mental Retardation Syndrome; MRXSL

- Potential model based on gene homology relationships. Phenotypic similarity to the human disease has not been tested. Frontotemporal Dementia; FTD   (MAPT) Parkinson Disease, Late-Onset; PD   (MAPT) Parkinson-Dementia Syndrome   (MAPT) Pick Disease of Brain   (MAPT) Supranuclear Palsy, Progressive, 1; PSNP1   (MAPT) - Potential model based on transgenic expression of a human gene that is associated with this disease. Phenotypic similarity to the human disease has not been tested. Angelman Syndrome; AS   (MECP2) Autism, Susceptibility to, X-Linked 3; AUTSX3   (MECP2) Encephalopathy, Neonatal Severe, Due to Mecp2 Mutations   (MECP2) Mental Retardation, X-Linked, Syndromic 13; MRXS13   (MECP2) Rett Syndrome; RTT   (MECP2)

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

Mapt^{tm1(Mecp2)Jae}/Mapt^{tm1(Mecp2)Jae}

        B6.Cg-Mapt^{tm1(Mecp2)Jae}

• growth/size phenotype
• decreased body weight   (MGI Ref ID J:182685)
• 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   (MGI Ref ID J:182685)
• enhanced paired-pulse facilitation
  • paired-pulse facilitation is augmented in mutants at the interstimulus intervals of 30 and 50 ms   (MGI Ref ID J:182685)
• reduced long term potentiation
  • high frequency stimulation-induced long term potentiation is attenuated in hippocampal slices from mutants compared to wild-type mice   (MGI Ref ID J:182685)
• behavior/neurological phenotype
• abnormal associative learning
  • mutants display consistent freezing levels across all extinction trials, indicating impaired extinction learning   (MGI Ref ID J:182685)
• • 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   (MGI Ref ID J:182685)
  • abnormal cued conditioning behavior
    • mutants exhibit an increase in freezing behavior in cue (auditory tone)-dependent fear conditioning 24 hours after training, suggesting enhanced associative learning   (MGI Ref ID J:182685)
    • 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   (MGI Ref ID J:182685)
    • 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   (MGI Ref ID J:182685)
• 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   (MGI Ref ID J:182685)
• impaired coordination
  • mutants spend less time on the rotarod than wild-type mice   (MGI Ref ID J:182685)
• increased anxiety-related response
  • 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   (MGI Ref ID J:182685)
  • in the dark/light test, mutants spend less time in the light side and more time in the dark side, indicating heightened anxiety   (MGI Ref ID J:182685)

The following phenotype information may relate to a genetic background differing from this JAX^® Mice strain.

Mapt^{tm1(Mecp2)Jae}/Mapt⁺

        involves: 129/Sv * C57BL/6

• normal phenotype
• no abnormal phenotype detected
  • heterozygous mice are fertile and healthy with no obvious abnormalities   (MGI Ref ID J:89593)

Mapt^{tm1(Mecp2)Jae}/Mapt^{tm1(Mecp2)Jae}

        involves: 129/Sv * C57BL/6

• mortality/aging
• *normal* mortality/aging
  • no premature death is seen in homozygotes   (MGI Ref ID J:89593)
• behavior/neurological phenotype
• abnormal sexual interaction
  • homozygotes do not mate   (MGI Ref ID J:89593)
• ataxia
  • gait ataxia is seen in homozygous mutants   (MGI Ref ID J:89593)
• excessive scratching
  • lesions are seen by 9 months probably as a result of excessive scratching   (MGI Ref ID J:89593)
• impaired balance
  • homozygotes display side-to-side swaying   (MGI Ref ID J:89593)
• tremors   (MGI Ref ID J:89593)
• growth/size phenotype
• cachexia
  • by 9 months homozygotes appear emaciated   (MGI Ref ID J:89593)
• postnatal growth retardation
  • by weaning homozygotes are 60% smaller than wild-type littermates probably as a result of an inability to compete for food   (MGI Ref ID J:89593)
  • after weaning homozygotes remain smaller than wild-type littermates   (MGI Ref ID J:89593)
• vision/eye phenotype
• cataracts
  • by 9 months homozygotes have developed cataracts   (MGI Ref ID J:89593)
• integument phenotype
• disheveled coat
  • by 9 months homozygotes appear disheveled   (MGI Ref ID J:89593)

View Research Applications

Research Applications

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

Developmental Biology Research
Neurodevelopmental Defects

Neurobiology Research
Alzheimer's Disease
      Tau (Mapt) mutants
Ataxia (Movement) Defects
Behavioral and Learning Defects
      high anxiety
Neurodegeneration
Neurodevelopmental Defects
      Rett's syndrome
Tremor Defects

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Mapttm1(Mecp2)Jae
Allele Name		targeted mutation 1, Rudolf Jaenisch
Allele Type		Targeted (knock-in)
Common Name(s)		Tau-Mecp2 ki;
Mutation Made By		Dr. Rudolf Jaenisch,   Whitehead Institute (MIT)
Strain of Origin		(C57BL/6 x 129S4/SvJae)F1
Expressed Gene		Mecp2, methyl CpG binding protein 2, mouse, laboratory
Gene Symbol and Name		Mapt, microtubule-associated protein tau
Chromosome		11
Gene Common Name(s)		AI413597; AW045860; DDPAC; FTDP-17; MAPTL; MSTD; MTBT1; MTBT2; Mtapt; PPND; RNPTAU; TAU; Tau; expressed sequence AI413597; expressed sequence AW045860; pTau;
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. [MGI Ref ID J:89593]

Genotyping

Genotyping Information

Genotyping Protocols

Mapt^{tm1(Mecp2)Jae}, Separated PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

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):6033-8. [PubMed: 15069197]  [MGI Ref ID 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):3109-17. [PubMed: 22378884]  [MGI Ref ID J:182685]

Health & husbandry

Health & Colony Maintenance Information

Colony Maintenance

Breeding & Husbandry	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.
Mating System	Wild-type x Heterozygote         (Female x Male)   26-OCT-12
	Heterozygote x Wild-type         (Female x Male)   26-OCT-12

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls

Control Information

	Control
	Wild-type from the colony
	000664 C57BL/6J
Considerations for Choosing Controls
Control Pricing Information for Genetically Engineered Mutant Strains.

Payment Terms and Conditions

Terms are granted by individual review and stated on the customer invoice(s) and account statement. These transactions are payable in U.S. currency within the granted terms. Payment for services, products, shipping containers, and shipping costs that are rendered are expected within the payment terms indicated on the invoice or stated by contract. Invoices and account balances in arrears of stated terms may result in The Jackson Laboratory pursuing collection activities including but not limited to outside agencies and court filings.

See Terms of Use tab for General Terms and Conditions

The Jackson Laboratory's Genotype Promise

The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX^® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX^® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX^® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project.

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Terms of Use

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