Overview

Also Known As:Prp-TDP-43^Q331K line 103

Prp-TDP-43^Q331K [~1.5x] transgenic line 103 mice have expression of a myc-tagged, human TAR DNA binding protein carrying the ALS-linked Q331K mutation (huTDP-43*Q331K) directed to brain and spinal cord by the mouse prion protein promoter. Along with the lower huTDP-43*Q331K expressing founder line (Prp-TDP-43^Q331K-low; Stock No. 017930), these Prp-TDP-43^Q331K [~1.5x] transgenic mice may be useful in studying motor dysfunction in the neurodegenerative disorder amyotrophic lateral sclerosis (ALS; Lou Gehrig's Disease), specifically motor dysfunction and L5 motor axon/lower motor neuron degeneration.

Donating Investigator

Dr. Don Cleveland, Ludwig Institute for Cancer Research (UCSD)

Genetic overview

Genetic Background	Generation
	N9pN1+N2F6 (2020-09-03 00:00:00)

Tg(Prnp-TARDBP*Q331K)103Dwc

Allele Type
Transgenic (Inserted expressed sequence, Humanized sequence)

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Research Applications

Research Tools
Neurobiology Research
Mouse/Human Gene Homologs

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Base Price

Starting at:

$278.00 Domestic price for female

356.51 Domestic price for breeder pair

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Details

Detailed Description

Prp-TDP-43^Q331K line 103 transgenic mice express a myc-tagged, human TAR DNA binding protein cDNA sequence modified to have the ALS-linked Q331K mutation (huTDP-43*Q331K), all under the direction of the mouse prion protein promoter (PrP). As expected for the PrP promoter, transgene expression is confined primarily to central nervous system (brain and spinal cord), with very low to no expression in other tested tissues (testis not examined). Anti-myc antibody staining shows huTDP-43*Q331K accumulation in the nuclei of neurons as well as glial cells of the spinal cord and brain, with a corresponding downregulation of endogenous mouse TDP-43. The transgene is flanked by loxP sites, allowing it to be removed by introduction of Cre recombinase if desired. The phenotype below describes Prp-TDP-43^Q331K transgenic mice from founder line 103 (Prp-TDP-43^Q331K [~1.5x]).
The Prp-TDP-43^Q331K [~1.5x] mice have moderate overexpression levels in total TDP-43 mRNA/protein, with an ~2.5-fold increase in total TDP-43 expression (huTDP-43*Q331K levels ~1.5-fold greater) compared to endogenous TDP-43 in non-transgenic mice. By three months of age, Prp-TDP-43^Q331K [~1.5x] mice develop adult-onset motor dysfunction (as measured by rotarod performance) accompanied by a loss of hindlimb-grip strength and the appearance of muscle fasciculations. Pathologically, Prp-TDP-43^Q331K [~1.5x] mice demonstrate ~30% loss of L5 motor axons and 30-45% loss of lower motor neurons by ten months of age (earlier timepoints not yet tested; May 2012). Of note, this latter phenotype is in contrast to Dr. Robert Baloh's Prp-TDP43^A315T transgenic mice that primarily display a loss of upper motor neurons (Stock No. 010700). Also note, this is in contrast to the founder line with low huTDP-43*Q331K overexpression (Prp-TDP-43^Q331K-low line 109; Stock No. 017930), that do not exhibit loss of motor axons or neurons.

Development

A full-length human TAR DNA binding protein (TARDBP or TDP-43) cDNA sequence was modified to have both an N-terminal myc tag and the glutamine to lysine substitution at amino acid 331 associated with familial ALS (huTDP-43*Q331K). This huTDP-43*Q331K cDNA sequence was inserted between exon 2 and exon 3 of mouse prion protein (PrP or Prnp) gene at two unique XhoI sites in the MoPrP.XhoI plasmid vector (ATCC#JHU-2). The resulting MoPrP.XhoI-^mychuTDP-43*Q331K transgene was flanked with loxP sites, and then injected into the pronuclei of fertilized C57BL6/C3H hybrid eggs, which were implanted into pseudopregnant female mice. Transgenic founder mice were bred to C57BL/6 mice, and founder line 103 was identified with ~2.5-fold greater total TDP-43 (~1.5-fold greater huTDP-43*Q331K) expression levels in spinal cord as compared to endogenous TDP-43 in non-transgenic mice. These Prp-TDP-43^Q331K [~1.5x] transgenic mice were bred with C57BL/6NCrl females for at least nine generations prior to sending to The Jackson Laboratory Repository. Upon arrival, transgenic mice were bred to C57BL/6NJ inbred mice (Stock No. 005304) for at least one generations to establish The Jackson Laboratory Repository colony.

Expression Data

Expressed Gene	TARDBP, TAR DNA binding protein, human
Expressed Gene	myc tag, myc tag,
Site of Expression

Control Suggestions

Noncarrier
005304 C57BL/6NJ

Additional Information

Considerations for Choosing Controls

Selected References

Arnold ES; Ling SC; Huelga SC; Lagier-Tourenne C; Polymenidou M; Ditsworth D; Kordasiewicz HB; McAlonis-Downes M; Platoshyn O; Parone PA; Da Cruz S; Clutario KM; Swing D; Tessarollo L; Marsala M; Shaw CE; Yeo GW; Cleveland DW. 2013. ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43. Proc Natl Acad Sci U S A 110(8):E736-45PubMed: 23382207 MGI: J:191785

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Genetics

Tg(Prnp-TARDBP*Q331K)103Dwc

Allele Symbol: Tg(Prnp-TARDBP*Q331K)103Dwc

Allele Name	transgene insertion 103, Don W Cleveland
Allele Type	Transgenic (Inserted expressed sequence, Humanized sequence)
Allele Synonym(s)	Prp-TDP-43^Q331K
Gene Symbol and Name	Tg(Prnp-TARDBP*Q331K)103Dwc, transgene insertion 103, Don W Cleveland
Gene Synonym(s)
Promoter	Prnp, prion protein, mouse, laboratory
Expressed Gene	TARDBP, TAR DNA binding protein, human
Expressed Gene	myc tag, myc tag,
Strain of Origin	C57BL/6 x C3H
Chromosome	UN
Molecular Note	A full-length human TAR DNA binding protein (TARDBP or TDP-43) cDNA sequence was modified to have both an N-terminal myc tag and the glutamine to lysine substitution at amino acid 331 associated with familial ALS (huTDP-43Q331K). This huTDP-43Q331K cDNA sequence was inserted between exon 2 and exon 3 of mouse prion protein (Prnp) gene. The resulting Prnp-TDP-43Q331K transgene was flanked with loxP sites. Founder line 103 was identified with approxiamately 2.5-fold greater total TDP-43 (1.5-fold greater huTDP-43Q331K) expression levels in spinal cord as compared to endogenous TDP-43 in non-transgenic mice.

Disease/Phenotype

Disease Terms

Research Areas By Phenotype

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

Research Tools
- Developmental Biology Research
  - Cre-lox System
- Cre-lox System
  - loxP-flanked Sequences
- Genetics Research
  - Mutagenesis and Transgenesis: Cre-lox System
- Neurobiology Research
Neurobiology Research
- Cortical Defects
- Neuromuscular defects
- Tremor Defects
- Myelination Defects
- Neurodegeneration
- Amyotrophic Lateral Sclerosis (ALS)
- Cre-lox System
  - loxP-flanked Sequences
- Ataxia (Movement) Defects
Mouse/Human Gene Homologs
- amyotrophic lateral sclerosis (ALS)

Mammalian Phenotype Terms by Genotype

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

Genotype: Tg(Prnp-TARDBPQ331K)103Dwc/?
involves: C57BL/6 C3H

behavior/neurological phenotype

decreased grip strength
- in hind limbs

impaired coordination
- motor deficits appear by 3 months when tested on a rotarod

limb grasping
- hind limb clasping develops by 3 months of age

tremors
- develop tremors around 3 months of age

nervous system phenotype

abnormal nervous system electrophysiology
- no differences from controls recorded at the thoracic T12 segment after stimulation of motor cortex

abnormal nervous system morphology

abnormal neuromuscular synapse morphology
- reduced number of gastrocnemius neuromuscular junction endplates

abnormal spinal cord dorsal column morphology
- minor degeneration

abnormal spinal cord lateral column morphology
- minor degeneration

abnormal spinal cord white matter morphology

decreased motor neuron number
- age dependent decrease in motor neuron number of about 35%
- most significant reductions in large caliber alpha motor axons at 10-12 months

muscle phenotype

abnormal muscle electrophysiology
- reduced myogenic motor evoked potentials after stimulation of motor cortex
- spontaneous gastrocnemius muscle fibrillations

abnormal muscle physiology

abnormal muscle regeneration
- regions of damaged muscle fibers and other areas of regeneration

skeletal muscle degeneration
- regions of damaged muscle fibers and other areas of regeneration

References

Arnold ES; Ling SC; Huelga SC; Lagier-Tourenne C; Polymenidou M; Ditsworth D; Kordasiewicz HB; McAlonis-Downes M; Platoshyn O; Parone PA; Da Cruz S; Clutario KM; Swing D; Tessarollo L; Marsala M; Shaw CE; Yeo GW; Cleveland DW. 2013. ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43. Proc Natl Acad Sci U S A 110(8):E736-45PubMed: 23382207 MGI: J:191785

Additional - Tg(Prnp-TARDBP*Q331K)103Dwc related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Sanger sequencing:human TARDBP*Q331K-SEQ
- Probe:Tg(TARDBP*Q331K)-Human Mut-EP
- Probe:Tg(TARDBP*331)-Human WT-EP
- Standard PCR:Tg(Prnp-TARDBP*)Dwc
- Genotyping resources and troubleshooting
Dietary Information
- LabDiet® 5K52 formulation (6% fat)
Breeding Considerations

When maintaining a live colony, hemizygous mice may be bred with wildtype (noncarrier) mice from the colony or with C57BL/6NJ inbred mice (Stock No. 005304). The donating investigator has not attempted to generate homozygous mice to date (May 2012).
- Additional Breeding and Husbandry Support
Mating System
- Noncarrier x Hemizygote
- Hemizygote x Noncarrier
Citation
When using the Prp-TDP-43^Q331K line 103 mouse strain in a publication, please cite the originating article(s) and include JAX stock #017933 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

FGB29 (Standard)

Pricing & Availability

Available

Domestic
International

Live Mouse

Age

Genotype

Price

weeks

Breeder Pair

Sex

Genotype

Price

Female
Male

Cryorecovery - Pricing

Service/Product	Description	Price
	Hemizygous or Non Carrier for Tg(Prnp-TARDBP*Q331K)103Dwc

Related Products and Services

Frozen Mouse Embryo	B6N.Cg-Tg(Prnp-TARDBP*Q331K)103Dwc/J Frozen Embryo	$2595.00
Frozen Mouse Embryo	B6N.Cg-Tg(Prnp-TARDBP*Q331K)103Dwc/J Frozen Embryo	$2595.00
Frozen Mouse Embryo	B6N.Cg-Tg(Prnp-TARDBP*Q331K)103Dwc/J Frozen Embryo	$3373.50
Frozen Mouse Embryo	B6N.Cg-Tg(Prnp-TARDBP*Q331K)103Dwc/J Frozen Embryo	$3373.50

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Also Known As:Prp-TDP-43Q331K line 103

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Expression Data

Control Suggestions

Additional Information

Selected References

Tg(Prnp-TARDBP*Q331K)103Dwc

Allele Symbol: Tg(Prnp-TARDBP*Q331K)103Dwc

Disease Terms

Research Areas By Phenotype

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

Mammalian Phenotype Terms by Genotype

Genotype: Tg(Prnp-TARDBP*Q331K)103Dwc/?involves: C57BL/6 * C3H

behavior/neurological phenotype

nervous system phenotype

muscle phenotype

References

Additional - Tg(Prnp-TARDBP*Q331K)103Dwc related

Genotyping Protocols

Dietary Information

Breeding Considerations

Mating System

Citation

Animal Health Reports

Live Mouse

Breeder Pair

Cryorecovery - Pricing

Related Products and Services

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms Of Use

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Also Known As:Prp-TDP-43^Q331K line 103

Genotype: Tg(Prnp-TARDBPQ331K)103Dwc/?
involves: C57BL/6 C3H