PrP-hFUS(WT) transgenic line PWT17 has expression of the wildtype human fused in sarcoma protein that is directed to brain and spinal cord (CNS neurons and astrocytes) by the mouse prion protein promoter. These mice may be useful in studying neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS; Lou Gehrig's Disease) and frontotemporal lobar degeneration (FTLD).
Lawrence J Hayward, University of Massachusetts Medical School
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(WT) transgene has the mouse prion protein (PrP) promoter directing expression of a human wildtype FUS.
The phenotype description below describes FVB-backcrossed PrP-hFUS(WT) mice from founder line PWT17. 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(WT) transgenic line PWT17 (Stock No. 020783). 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 no neuropathological/electromyographical abnormalities or progressive paralysis. However, half of the hemizygotes die by ~203 days of age: this premature lethality is associated with an acute moribund state, poor feeding, and death within several days to a week.
Hemizygous mice have ~2 copies of the transgene, with hFUS expression levels in brain and spinal cord that are similar to endogenous mouse FUS levels.
The spinal motor neurons from 5-6 months old hemizygotes show that both hFUS(WT) and mouse PRMT1 expression is predominantly in the nucleus, similar to that observed for endogenous mouse FUS and PRMT1 in nontransgenic littermates. Nuclear expression of hFUS is reported in cortical neurons, deep cerebellar nuclei, lumbar spinal cord anterior horn cells, hippocampal neurons, and cerebellar granule cells. No inclusions are reported (via FUS immunohistochemistry, ubiquitin markers or p62 markers). The phenotype of homozygous mice is not characterized to date (October 2014).
The PrP-hFUS(WT) transgene was designed by Dr. Lawrence J. Hayward (University of Massachusetts Medical School). First, a cDNA sequence was obtained encoding the wildtype human fused in sarcoma protein. The wildtype hFUS 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(WT) 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 PWT17 was identified with ~2 copies of the transgene. These PrP-hFUS(WT) 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 six additional generations. The C57BL/6J-congenic PrP-hFUS(WT) transgenic line PWT17 is Stock No. 020783.
In December 2014, a 32 SNP panel analysis (27 markers covering all 19 chromosomes and the X chromosome, as well as 5 markers that distinguish between the C57BL/6J and C57BL/6N substrains), was performed on a cohort of live mice (generation N1+N6) at The Jackson Laboratory Repository. This revealed 1 of the 27 markers on chromosome 13 [~15.3 cM] that was not fixed for C57BL/6 allele-type (i.e., still segregating for FVB/SJL allele-type marker). In addition, 2 of the 5 markers, one on chromosome 11 [~4.4 Mb] and one on chromosome 19 [~50 Mb], were not fixed for C57BL/6 allele-type (i.e., still segregating for C57BL/6N/FVB/SJL allele-type marker). Taken together, these data suggest the generation N1+N6 mice are ~90% C57BL/6. As of June 2015, three additional backcrosses have been performed, and the live colony is generation N1+N9. SNP results from this generation are in progress.
|Expressed Gene||FUS, fused in sarcoma , human|
|Site of Expression|
|Allele Name||transgene insertion 17, Lawrence Hayward|
|Allele Type||Transgenic (Inserted expressed sequence, Humanized sequence)|
|Allele Synonym(s)||FUSWT; line PWT17|
|Gene Symbol and Name||Tg(Prnp-FUS)17Ljh, transgene insertion 17, Lawrence Hayward|
|Promoter||Prnp, prion protein, mouse, laboratory|
|Expressed Gene||FUS, fused in sarcoma , human|
|Strain of Origin||(C57BL/6 x SJL)F2|
|Molecular Note||The transgenic construct contains a cDNA sequence encoding the wild-type human fused in sarcoma protein (FUS). The cDNA sequence is inserted between exon 2 and exon 3 of mouse prion protein (PrP or Prnp) gene. Line PWT17 is identified with ~2 copies of the transgene and results in a 2-fold FUS overexpression.|
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.
When using the PrP-hFUS(WT) line PWT17 mouse strain in a publication, please cite the originating article(s) and include JAX stock #020783 in your Materials and Methods section.
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