B6JOlaHsd.129P2-Ercc1^tm2Jhjh/J

Stock number: 040164
Product name: Ercc1^Δ , ERCC1^*292 , Ercc1^d , Ercc1^delta , Ercc1^m
Strain synonyms: B6JOlaHsd Ercc1^Δ
Research areas: Cell Biology Research, Developmental Biology Research, Metabolism Research, Neurobiology Research

Description

ERCC1^*292 (also called Ercc1^delta or Ercc1^d) mice demonstrate a partial inactivation of the mouse Ercc1 (excision repair cross-complementing rodent repair deficiency, complementation group 1) gene. Protein is truncated immediately after the Escherichia coli nucleotide excision repair (NER) endonuclease UvrC-homologous region, resulting in a seven amino-acid carboxy-terminal deletion. This is a DNA repair-deficient mouse model that displays features of accelerated aging in multiple tissues including liver, kidney, and the central nervous system (CNS).

Detailed description

ERCC1^*292 (also called Ercc1^delta or Ercc1^d) mice demonstrate a partial inactivation of the mouse Ercc1 (excision repair cross-complementing rodent repair deficiency, complementation group 1) gene. A neomycin cassette was introduced to intron 9 and a TAG stop codon and diagnostic BamHI restriction site were created in exon 10, preventing the expression of the last 7 amino acids (two of which are in the ERCC1 essential domain). Transcription, at levels that are approximately 15% that of wildtype, and mRNA processing remain intact. Neomycin is excluded from the protein product by splicing. The encoded stable protein terminates immediately after the Escherichia coli nucleotide excision repair (NER) endonuclease UvrC-homologous region. Transcription of an overlapping antisense gene (Polr1g; also called Ase1) is unaffected by the Ercc1 targeting event.

ERCC1^*292 (Ercc1^d) homozygotes are born in reduced numbers (many dying by embryonic day 13.5) when bred in a pure C57BL/6 or FVB background and show retarded growth. Therefore, experimental animals were only bred on a C57BL/6-FVB F1 genetic background by the donating laboratory. On a C57BL/6 genetic background, homozygotes are reported to have a life span of up to 6 months.

Ercc1^d/- mice (Ercc1^d x Ercc1^- (Stock No. 040163)) exhibit an absence of subcutaneous fat, early onset of ferritin deposition in the spleen, kidney malfunction, nuclear abnormalities in the kidney and liver, neurodegeneration and cardiovascular aging, and compromised nucleotide excision repair (NER). Mouse embryonic fibroblasts (MEFs) derived from homozygotes grow three times more slowly than wildtype fibroblasts in vitro. (Weeda, 1997; PMID 9197240)

ERCC1^*292 heterozygotes on a mixed FVB:C57BL/6J genetic background demonstrate decreased striatal dopaminergic innervation in the caudate putamen, paralleled by increased tyrosine hydroxylase (TH) expression in substantia nigra pars compacta (SNpc) neuronal bodies. (PMID 27210754, Fig. 2)

This mutation is also available on a predominantly FVB genetic background (see Stock No. 040165), with homozygous animals reportedly surviving up to ~78 days.

The donating laboratory wishes to note that all of their ERCC1^*292 (Ercc1^delta, Ercc1^d) compound mutant experiments (PMID 27556946, PMID 36756698, PMID 38498063, PMID 22953029, PMID 38689513, PMID 38451018) were performed on an F1 hybrid genetic background. This hybrid background was derived from crosses of C57BL/6JOlaHsd-background mutant animals with FVB/NHanHsd-background mutant animals (e.g. Ercc1^+/- FVB (Stock No. 040163) x Ercc1^d/+ C57BL/6). The contributing single mutant alleles were maintained independently through crosses of heterozygotes with C57BL/6JOlaHsd or FVB/NHanHsd inbred mice rather than wildtype animals from within their colonies (e.g. Ercc1^d/+ C57BL/6 x WT (Ercc1^+/+) C57BL/6). They did not maintain homozygous colonies and their F1 mice were not further intercrossed.

Development

A neomycin cassette was introduced to intron 9 and a TAG stop codon and diagnostic BamHI restriction site were created in exon 10 (CCCTTCCTC -> TAGGATCCC) via homologous recombination in 129P2/OlaHsd-derived E14 embryonic stem (ES) cells. Resultant mice were backcrossed to C57BL/6JOlaHsd for more than 75 generations by the donating laboratory prior to sending ERCC1^*292 females and males to The Jackson Laboratory. Upon arrival, those females and males were used to rederive the colony. Subsequently, embryos will be cryopreserved.

The encoded stable protein terminates immediately after the Escherichia coli nucleotide excision repair (NER) endonuclease UvrC-homologous region. Transcription of an overlapping antisense gene (Polr1g; also called Ase1) is unaffected by the Ercc1 targeting event.

Allele

Symbol: Ercc1^tm2Jhjh
Name: targeted mutation 2, Jan H J Hoeijmakers
MGI accession ID: MGI:2183945
Generation method: Targeted
Attributes: Hypomorph
Synonyms: ERCC1^*292; Ercc1^d; Ercc1^delta; Ercc1^m
Marker symbol: Ercc1
Marker name: excision repair cross-complementing rodent repair deficiency, complementation group 1
Marker synonyms: COFS4; Ercc-1; RAD10; UV20
Chromosome: 7
Strain of origin: 129P2/OlaHsd
Molecular note: A stop codon was introduced at position 292 to shorten the protein by 7 residues, 2 of which are in the essential domain. Expression and sequence analysis showed message to be transcribed and processed properly in homozygous mutant mice. RT-PCR analysis revealed levels of transcript to be approximately 15% of those in wild-type mice. Further analysis showed that transcription of the antisense gene was unaffected by the targeting event.