B6.129S2-Disc1^{tm1(DISC1/DISC1FP1,DISC1FP1/DISC1,DISC1)Xzho}/J

Stock number: 030517
Product name: DISC1-Boymaw
Research areas: Neurobiology Research

Description

DISC1^H mice contain a floxed cassette consisting of the two human fusion genes, DB7 and BD13, followed by an SV40 polyadenylation signal and a human wildtype DISC1 cDNA, inserted downstream of the start codon of the murine Disc1 gene. These mice may be useful when studying schizophrenia and other major psychiatric disorders.

 

Detailed description

Translocation of human genes on chromosome 1 and chromosome 11 were found to co-segregate with a 70% penetrance for major depression, schizophrenia and other psychiatric disorders in a Scottish family. DISC1 (disrupted-in-schizophrenia 1) was found to be at the breakpoint on chromosome 1. DISC1 plays important roles in neuronal cell proliferation, differentiation, migration, maturation and synaptic functions. Another gene was interrupted in this translocation, DISC1FP1 (DISC1 fusion partner 1 or Boymaw). DISC1FP1 or Boymaw encodes a small protein that inhibits mitochondrial functions. After translocation, the fusion genes DISC1-Boymaw (DB7) and Boymaw-DISC1 (BD13) are generated. DB7 is insoluble, and previously insoluble DISC1 was been found in the postmortem brains of patients with schizophrenia, major depression and bipolar disorder.

DISC1^H mice contain a floxed cassette consisting of the two human fusion genes, DB7 and BD13, followed by an SV40 polyadenylation signal and a human wildtype DISC1 cDNA. This cassette was inserted just downstream of the start codon of the murine Disc1 gene.

Protein translation is decreased in the hippocampus and in cultured primary neurons from the brain. Expression of GAD67 (glutamate decarboxylase 1), NMDAR1 (Grin1, glutamate receptor, ionotropic, NMDA1 (zeta 1)), and PSD95 (Dlg4, discs, large homolog 4) proteins are also reduced. These genes are critical for pathophysiology of schizophrenia and other psychiatric disorders, and play roles in GABAergic and glutamatergic neurotransmission as well as synaptogenesis. Impaired mitochondrial function and reduced protein synthesis activity are evident. Mice also exhibit abnormal erythropoiesis, which was reported to associate with depression in humans. When prepulse inhibition was conducted with short interstimulus intervals, mutant mice displayed prepulse facilitation. Male mice have prolonged and increased responses to the NMDA receptor antagonist, ketamine.

Interestingly, C57BL/6 mice carry wildtype Disc1 while 129 mice have a frame-shift mutation in exon 6 creating a null. Behavioral studies have been carried out on an F1 129S/C57 background. In the F1 generation, both wild-type and the DISC1^H heterozygous mice carry one allele of mouse wild-type Disc1 gene. Mice that are homozygous for this allele are viable and fertile. When bred to mice that express tissue-specific Cre recombinase, resulting offspring will have the DB7 and BD13 fusion genes deleted in the cre-expressing tissues, and wildtype human DISC1 will be expressed.

Development

DISC1^H mice contain a floxed cassette consisting of two human fusion genes, disrupted-in-schizophrenia 1 (DISC1)-DISC1 fusion partner 1 or Boymaw (DISC1FP1) (termed DB7) and Boymaw-DISC1 (termed BD13), connected with an internal ribosome entry site (IRES) and followed by an SV40 polyadenylation signal. This cassette was placed just downstream of the start codon of the murine Disc1 gene, and a human wildtype DISC1 cDNA and a neomycin resistance cassette were inserted downstream of the floxed cassette. The construct was electroporated into 129S2/SvPasCrl-derived embryonic stem (ES) cells. Correctly targeted ES cells were injected into blastocysts and resulting chimeric mice were bred with 129S2/SvPasCrl mice. Resulting DISC1^H mice were further backcrossed to C57BL/6J mice for nine generations. Upon arrival at The Jackson Laboratory Repository, sperm was cryopreserved. To establish our live colony, an aliquot of frozen sperm was used to fertilize C57BL/6J oocytes (Stock No. 000664).

Allele

Symbol: Disc1^{tm1(DISC1/DISC1FP1,DISC1FP1/DISC1,DISC1)Xzho}
Name: targeted mutation 1, Xianjin Zhou
MGI accession ID: MGI:5648808
Generation method: Targeted
Attributes: Conditional ready (e.g. floxed); Null/Knockout; Inserted expressed sequence; Humanized sequence
Synonyms: DISC1^H
Marker symbol: Disc1
Marker name: disrupted in schizophrenia 1
Marker synonyms: C1orf136; SCZD9
Chromosome: 8
Strain of origin: 129S2/SvPasCrl
Expressed genes: DISC1,DISC1 scaffold protein,human; DISC1FP1,DISC1 fusion partner 1,human
Site of expression: Neuronal cells.
Molecular note: A floxed cassette containing two human fusion genes, DISC1/DISC1FP1 (DB7) and DISC1FP1/DISC1 (BD13), connected with an IRES followed by a human DISC1 cDNA capped with a splice acceptor site replaced part of exon 1 downstream of the start site via homologous recombination.