These DISC1-cc transgenic mice have expression of a tamoxifen-inducible, LBDG521R-DISC1-cc fusion protein directed to the branches of cortex, hippocampus, striatum, and cerebellum neurons (cytoplasm) of the forebrain by the mouse CaMKIIα promoter. These mice allow inducible and reversible expression of a dominant-negative isoform of disrupted-in-schizophrenia-1, and may be useful to study how interruption of DISC1 function at specific time points during brain development affects schizophrenia or other neurological disorders.
Alcino J. Silva, University of California, Los Angeles
Mice hemizygous for this DISC1-cc transgene are viable and fertile, with expression of a tamoxifen-inducible, LBDG521R-DISC1-cc fusion protein directed to the branches of cortex, hippocampus, striatum, and cerebellum neurons (cytoplasm) of the forebrain by the mouse CaMKIIα promoter. The fusion protein consists of a truncated mutant isoform of the mouse disrupted-in-schizophrenia-1 gene (DISC1-cc; containing only residues (671-852) critical for NUDEL and Lis1 binding) and a mutant form of the human estrogen receptor ligand binding domain (LBDG521R; which is unable to bind its natural ligand, estrogen, at physiological concentrations but will bind the synthetic ligand, 4-hydroxytamoxifen). Prior to tamoxifen administration, the fusion protein is sequestered by chaperone proteins and is degraded. Upon tamoxifen binding, the fusion protein is released from the chaperone proteins and is then free to compete/interfere with endogenous Disc1 binding, thus having a dominant-negative function. Early postnatal, but not adult, tamoxifen-induced expression of the fusion protein results in a cluster of schizophrenia-related phenotypes, including reduced hippocampal dendritic complexity, depressive-like traits, abnormal spatial working memory, and reduced sociability. Of note, the homozygous phenotype is not yet characterized (July 2012) as the donating investigator has not attempted to breed hemizygous mice together to make homozygous mice.
The DISC1-cc transgene was designed with a CaMKIIα promoter controlling an HA-tagged, LBDG521R-DISC1-cc fusion protein. Specifically, this transgene contains a mouse α-calmodulin kinase II promoter, hybrid intron in the 5' untranslated leader, HA virus-tag sequence, mutant form of the estrogen ligand biding domain (LBDG521R) cDNA fused 5' to a truncated mouse DISC1 cDNA (DISC1-cc; encoding the C-terminal protein residues 671-852), and polyA sequence. This transgene was injected into the pronuclei of C57BL/6 zygotes. The resulting chimeric founders (line 2698.1) were subsequently backcrossed to C57BL/6NTac mice for at least nine generations prior to sending to The Jackson Laboratory Repository in 2012. Upon arrival, transgenic mice were bred at least one generation to C57BL/6NJ inbred mice (Stock No. 005304) to establish The Jackson Laboratory Repository colony.
|Expressed Gene||ESR1, estrogen receptor 1, human|
|Site of Expression|
|Allele Name||transgene insertion 2698.1, Alcino J Silva|
|Allele Type||Transgenic (Inserted expressed sequence)|
|Allele Synonym(s)||DISC-cc; LBDG521R-DISC1-cc|
|Gene Symbol and Name||Tg(Camk2a-ESR1/Disc1*)2698.1Sva, transgene insertion 2698.1, Alcino J Silva|
|Gene Synonym(s)||DISC-cc; LBDG521R-DISC1-cc|
|Promoter||Camk2a, calcium/calmodulin-dependent protein kinase II alpha, mouse, laboratory|
|Expressed Gene||ESR1, estrogen receptor 1, human|
|Strain of Origin||C57BL/6|
|Molecular Note||The transgene construct is composed of a mouse a-calmodulin kinase II promoter, a hybrid intron in the 5' untranslated leader, a HA virus-tag sequence, and a mutant form of the estrogen ligand biding domain (LBDG521R) cDNA fused 5' to a truncated mouse DISC1 cDNA (DISC1-cc; encoding the C-terminal protein residues 671-852), and a polyA sequence. Upon tamoxifen induction of fusion gene expression, the LBDG521R-DISC1-cc fusion protein is directed to the cortex, hippocampus, striatum, and cerebellum by the CaMKIIa promoter. Immunohistochemical expression of mutant protein is observed in the forebrain in the branches and cytoplasm of neurons.|
|Mutations Made By|| |
Alcino Silva, University of California, Los Angeles
When maintaining a live colony, hemizygotes are bred to wildtype (noncarrier) mice from the colony or to C57BL/6NJ inbred mice (Stock No. 005304). The donating investigator has not attempted to breed hemizygous mice together to make homozygous for the transgene (July 2012).
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