Overview

Also Known As:PrP-hFUS(R495X) line PX78

PrP-hFUS*R495X transgenic line PX78 has expression of a truncated mutant form of fused in sarcoma protein that is directed to brain and spinal cord (CNS neurons and astrocytes) by the mouse prion protein promoter. The hFUS*R495X mutation in the nuclear-localization domain is associated with significant cytoplasmically-mislocalized hFUS and amyotrophic lateral sclerosis (ALS). These mice may be useful in studying neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS; Lou Gehrig's Disease) and frontotemporal lobar degeneration (FTLD).

Donating Investigator

Lawrence J Hayward, University of Massachusetts Medical School

Genetic overview

Genetic Background	Generation

Tg(Prnp-FUS*R495X)78Ljh

Allele Type
Transgenic (Inserted expressed sequence, Humanized sequence)

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Research Applications

Neurobiology Research
Research Tools
Mouse/Human Gene Homologs
Cell Biology Research

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Base Price

Starting at:

$2,854.50 Domestic price Cryo Recovery

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Details

Detailed Description

Nucleo-cytoplasmic shuttling of fused in sarcoma (FUS) occurs by a nuclear localization signal (NLS). The majority of clinical amyotrophic lateral sclerosis (ALS; Lou Gehrig's Disease) and frontotemporal lobar degeneration (FTLD)-associated FUS mutations occur in its C-terminal NLS sequence.

The PrP-hFUS*R495X transgene has the mouse prion protein (PrP) promoter directing expression of an ALS-associated human R495X truncation mutant (hFUS*R495X) lacking its C-terminal NLS; resulting in significant hFUS mislocalization (abnormal accumulation within the cytoplasm).

The phenotype description below describes FVB-backcrossed PrP-hFUS*R495X mice from founder line PX78. In an attempt to offer transgenic models on well-characterized or multiple genetic backgrounds, transgenes are frequently moved to a genetic background different from that on which they were first characterized. This is the case for the C57BL/6J-congenic PrP-hFUS*R495X transgenic line PX78 (Stock No. 019728). It should be noted that the phenotype could vary from that described below. We will modify the strain description if necessary as published results become available.

The donating investigator reports that hemizygous mice are viable and fertile, with cytoplasmic mislocalization of hFUS*R495X (as shown by immunostaining with a hFUS-specific antibody). Hemizygous mice have ~10-12 copies of the transgene, with ~4-fold greater hFUS expression levels in brain and spinal cord compared to endogenous mouse FUS levels.

In addition, robust cytoplasmic accumulation of hFUS is reported in cortical neurons, deep cerebellar nuclei, lumbar spinal cord anterior horn cells and hippocampal neurons.

Surprisingly, neurons more than one year old appear to tolerate the cytoplasmic hFUS without evidence of abnormal morphological features or obvious neuronal loss. No inclusions are reported (via FUS immunohistochemistry, ubiquitin markers or p62 markers), and cytoplasmic hFUS expression is not shown to alter the normal nuclear prominence of TDP-43 staining. By 8-12 months, hemizygous mice can exhibit neuropathological/electromyographical abnormalities in hindlimb muscles (fibrillation potentials, muscle denervation and reduction in motor unit number estimation).

Hemizygotes sporadically develop a swollen large intestine and evidence of paralytic ileus that cause premature lethality (50% of the original cohort died by ~118 days of age). Homozygous mice were more severely affected, with lower body mass and earlier premature lethality (50% of the original cohort lost by ~59 days of age).

Development

The PrP-hFUS*R495X transgene was designed by Dr. Lawrence J. Hayward (University of Massachusetts Medical School). First, a cDNA sequence was obtained encoding the human fused in sarcoma R495X truncation mutant (hFUS*R495X) that is associated with amyotrophic lateral sclerosis (ALS). The hFUS*R495X mutation abrogates a putative nuclear localization signal at the C-terminus of FUS, resulting in significant hFUS mislocalization within the cytoplasm. The hFUS*R495X 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.Xho plasmid (ATCC#JHU-2). The ~13.6 kbp linearized PrP-hFUS*R495X transgene was microinjected into (C57BL/6 x SJL)F2 hybrid mouse embryos at UMass Transgenic Animal Modeling Core facility. Transgenic founders were bred to FVB mice, and founder line PX78 was identified with 10-12 copies of the transgene. These PrP-hFUS*R495X transgenic mice were bred with FVB mice for at least four generations. Next, transgenic mice were bred to C57BL/6J for one generation, and then sent to The Jackson Laboratory Repository in 2013. Upon arrival, transgenic mice were backcrossed with C57BL/6J inbred mice (Stock No. 000664) for at least eight additional generations. The C57BL/6J-congenic PrP-hFUS*R495X transgenic line PX78 is Stock No. 019728.

Expression Data

Expressed Gene	FUS, fused in sarcoma , human
Site of Expression

Control Suggestions

Noncarrier

Additional Information

Considerations for Choosing Controls

Selected References

Tibshirani M; Tradewell ML; Mattina KR; Minotti S; Yang W; Zhou H; Strong MJ; Hayward LJ; Durham HD. 2015. Cytoplasmic sequestration of FUS/TLS associated with ALS alters histone marks through loss of nuclear protein arginine methyltransferase 1. Hum Mol Genet 24(3):773-86PubMed: 25274782 MGI: J:218094

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Genetics

Tg(Prnp-FUS*R495X)78Ljh

Allele Symbol: Tg(Prnp-FUS*R495X)78Ljh

Allele Name	transgene insertion 78, Lawrence Hayward
Allele Type	Transgenic (Inserted expressed sequence, Humanized sequence)
Allele Synonym(s)	FUS^R495X; line PX78
Gene Symbol and Name	Tg(Prnp-FUS*R495X)78Ljh, transgene insertion 78, Lawrence Hayward
Gene Synonym(s)
Promoter	Prnp, prion protein, mouse, laboratory
Expressed Gene	FUS, fused in sarcoma , human
Strain of Origin	(C57BL/6 x SJL)F2
Chromosome	UN
Molecular Note	The transgenic construct contains a cDNA sequence encoding the human fused in sarcoma R495X truncation mutant (hFUS*R495X) associated with amyotrophic lateral sclerosis (ALS). The cDNA sequence was inserted between exon 2 and exon 3 of mouse prion protein (PrP or Prnp) gene. The mutation abrogates a putative nuclear localization signal at the C-terminus of FUS, resulting in significant hFUS mislocalization within the cytoplasm. Line PX78 is identified with 10-12 copies of the transgene and results in a 3-5-fold FUS overexpression.

Disease/Phenotype

Disease Terms

Research Areas By Phenotype

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

Neurobiology Research
- Myelination Defects
  - peripheral neuropathy
- Tremor Defects
- Ataxia (Movement) Defects
- Cortical Defects
- Amyotrophic Lateral Sclerosis (ALS)
- Neuromuscular defects
- Behavioral and Learning Defects
- Neurodegeneration
Research Tools
- Neurobiology Research
- Immunology, Inflammation and Autoimmunity Research
Mouse/Human Gene Homologs
- amyotrophic lateral sclerosis (ALS)
Cell Biology Research
- Transcriptional Regulation

Mammalian Phenotype Terms by Genotype

References

Tibshirani M; Tradewell ML; Mattina KR; Minotti S; Yang W; Zhou H; Strong MJ; Hayward LJ; Durham HD. 2015. Cytoplasmic sequestration of FUS/TLS associated with ALS alters histone marks through loss of nuclear protein arginine methyltransferase 1. Hum Mol Genet 24(3):773-86PubMed: 25274782 MGI: J:218094

Additional - Tg(Prnp-FUS*R495X)78Ljh related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Standard PCR:Tg(Prnp-FUS*R495X)78Ljh
- Genotyping resources and troubleshooting
Breeding Considerations

Transgenic mice were bred to C57BL/6J inbred mice (Stock No. 000664) for at least eight generations to establish this congenic strain. When maintaining the live congenic colony, hemizygous mice may be bred with wildtype (noncarrier) mice from the colony or with C57BL/6J mice.
- Additional Breeding and Husbandry Support
Citation
When using the PrP-hFUS(R495X) line PX78 mouse strain in a publication, please cite the originating article(s) and include JAX stock #019728 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
	Hemizygous or non carrier for Tg(Prnp-FUS*R495X)78Ljh

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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. We do not guarantee breeding performance and therefore suggest that investigators order more than one breeding pair to avoid delays in their research.

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Also Known As:PrP-hFUS(R495X) line PX78

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Expression Data

Control Suggestions

Additional Information

Selected References

Tg(Prnp-FUS*R495X)78Ljh

Allele Symbol: Tg(Prnp-FUS*R495X)78Ljh

Disease Terms

Research Areas By Phenotype

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

Mammalian Phenotype Terms by Genotype

References

Additional - Tg(Prnp-FUS*R495X)78Ljh 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

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