Distribution from cryopreservation on hold due to genetic quality control.
FUS-R521C line 3313 expresses a FLAG-tagged, autosomal dominant mutant isoform of fused in sarcoma protein directed to brain and spinal cord (CNS neurons and astrocytes) by the Syrian hamster prion protein promoter. The hFUS*R521C mutation in the nuclear-localization domain is associated with familial amyotrophic lateral sclerosis (FALS). These mice may be useful in studying neurodegenerative disorders such as FALS (Lou Gehrig's Disease).
Eric J Huang, University of California at San Francisco
The description below is the published phenotype of FUS-R521C line 3313 mice from generations N1 (~75% C57BL/6) and N2 (~88% C57BL/6). The donating investigator sent N2 animals to The Jackson Laboratory Repository. Upon arrival, transgenic mice were bred to B6SJLF1/J mice (Stock No. 100012) for at least one generation, and thereafter maintained by breeding hemizygous females with wildtype (noncarrier) males from the colony. Therefore, our live colony of FUS-R521C line 3313 (Stock No. 026406) is expected to be ~60-70% C57BL/6. 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.
Nucleo-cytoplasmic shuttling of fused in sarcoma (FUS) occurs by a nuclear localization signal (NLS). It is estimated that ~5% of familial amyotrophic lateral sclerosis (FALS; Lou Gehrig's Disease) cases are associated with FUS mutations, with the majority of the mutations occurring in its C-terminal NLS sequence. The SHaPrP-FLAG-hFUS*R521C transgene has the Syrian hamster prion protein (SHaPrP) promoter directing expression of a FLAG-tagged, ALS-associated human R521C autosomal dominant isoform (hFUS*R521C) with a mutation in the NLS.
Hemizygous mice from SHaPrP-FLAG-hFUS*R521C transgenic line 3313 (also called FUS-R521C line 3313) show hFUS*R521C expression levels similar to that of endogenous mouse FUS in brain and spinal cord. Hemizygotes also have increased total FUS (hFUS*R521C + wildtype FUS) compared to nontransgenic mice. Hemizygous tissues show FLAG-tagged FUS*R521C expression in cytoplasm and nucleus; although it is predominantly in the nuclei of spinal motor neurons, with a relatively low abundance in the neuronal cytoplasm. The mutant FUS*R521C protein forms a stable complex with wildtype FUS proteins and interferes with the normal interactions between FUS and histone deacetylase 1 (HDAC1). In addition, mutant FUS*R521C protein also interferes with RNA splicing. Consequently, hemizygous mice exhibit evidence of increase in DNA damage and RNA splicing defects that contribute to severe dendritic and synaptic defects in both spinal motor neurons and cortical neurons.
The donating investigator describes mice from generation N1 (~75% C57BL/6) and N2 (~88% C57BL/6) have similar onset of neuropathological phenotype, but survival improves as more backcrosses onto C57BL/6 are performed. Specifically, half of all hemizygous mice exhibit neuropathological phenotype (motor behavioral abnormalities, severe spastic paraplegia, tremor, reduced muscle mass, abnormal gait and motor coordination) by ~30 days for generation N1 and ~40 days for generation N2. Symptomatic hemizygotes have reduced lifespan: 50% of generation N1 die by ~50-75 days of age, while 50% of generation N2 die by ~130-180 days of age. Surviving hemizygotes from generation N1 or N2 exhibit persistent tremor and motor symptoms (such as gait problems), but females can otherwise be used at 3-6 months of age for breeding. FUS+ ubiquitin+ cytoplasmic inclusions are detected in very small number (less than 5%) of spinal motor neurons in generation N1 or N2 hemizygous mice.
The donating investigator reports hemizygous females are fertile but males do not breed. The phenotype of homozygous mice is not characterized to date (March 2015). In 2016, The Jackson Laboratory Repository reports that hemizygous sperm is viable, fertile and suitable for in vitro fertilization. In 2017, The Jackson Laboratory Repository reports that breeding hemizygous males to wildtype (non-carrier) females results in transgenic offspring at a rate (~33%) that is less than Mendelian inheritance expectations.
The SHaPrP-FLAG-hFUS*R521C transgene was designed by Dr. Eric J. Huang (University of California at San Francisco). First, a cDNA sequence was obtained encoding an N-terminal FLAG-tagged, human fused in sarcoma R521C autosomal dominant mutant isoform (hFUS*R521C) that is associated with familial amyotrophic lateral sclerosis (FALS). Specifically, hFUS*R521C encodes an autosomal dominant missense mutation in the nuclear localization signal at the C-terminus of FUS. The FLAG-tagged hFUS*R521C cDNA sequence (~1.5 kbp) was positioned downstream of the Syrian (golden) hamster prion protein (SHaPrP or Prnp) promoter sequences by insertion into SHaPrP exon 3. The SHaPrP-FLAG-hFUS*R521C transgene (~3.7 kbp) was microinjected into B6SJL oocytes. Transgenic male founders were bred to C57BL/6J female mice. Mice from both founder lines (#3313 and #3303) showed comparable expression levels of FLAG-tagged FUS-R521C protein in brain and spinal cord, and developed similar neurological abnormalities. Because mice from founder line 3313 had a higher propensity of developing disease and dying from their disease, mice from line 3313 were characterized. SHaPrP-FLAG-hFUS*R521C transgenic line 3313 (also called FUS-R521C line 3313) was bred with C57BL/6J for one additional generation, and hemizygous female mice from generation N2 were sent to The Jackson Laboratory Repository in 2015. The coat color was black and agouti. Upon arrival, mice were bred to B6SJLF1/J hybrid mice (Stock No. 100012) for at least one generation to establish our live colony. Thereafter, the colony was maintained by breeding hemizygous females with wildtype (noncarrier) males from the colony.
|Expressed Gene||FUS, fused in sarcoma , human|
|Site of Expression|
|Allele Name||transgene insertion 3313, Eric J Huang|
|Allele Type||Transgenic (Inserted expressed sequence, Humanized sequence, Modified isoform(s))|
|Gene Symbol and Name||Tg(Prnp-FUS*R521C)3313Ejh, transgene insertion 3313, Eric J Huang|
|Promoter||Prnp, prion protein, hamster|
|Expressed Gene||FUS, fused in sarcoma , human|
|Strain of Origin||(C57BL/6 x SJL)F1|
|Molecular Note||The transgenic construct contains an N-terminal FLAG-tagged, human fused in sarcoma R521C autosomal dominant mutant isoform (hFUS*R521C) that is associated with familial amyotrophic lateral sclerosis (FALS). The isoform encodes an autosomal dominant missense mutation in the nuclear localization signal at the C-terminus of FUS. The FLAG-tagged hFUS*R521C cDNA sequence (~1.5 kbp) was positioned downstream of the Syrian (golden) hamster prion protein (SHaPrP or Prnp) promoter sequences by insertion into SHaPrP exon 3.|
The donating investigator reports hemizygous females are fertile but males do not breed. When maintaining the live colony on a C57BL/6;SJL genetic background, hemizygous females may be bred with wildtype (noncarrier) males from the colony. The phenotype of homozygous mice is not characterized to date (March 2015). In 2016, The Jackson Laboratory Repository reports that hemizygous sperm is viable, fertile and suitable for in vitro fertilization. In 2017, The Jackson Laboratory Repository reports that breeding hemizygous males to wildtype (non-carrier) females results in transgenic offspring at a rate (~33%) that is less than Mendelian inheritance expectations.
When using the FUS-R521C line 3313 mouse strain in a publication, please cite the originating article(s) and include JAX stock #026406 in your Materials and Methods section.
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