CRISPR/Extreme Genome Editing technology was used to develop Tet(TorA) mice, which have a loxP-flanked STOP cassette followed by the tetracycline operator (tetO) inserted upstream of the start codon of the endogenous torsin family 1, member A (Tor1a) gene. Tor1a encodes an ATPase found primarily in the endoplasmic reticulum and nuclear envelope. Mutations in Tor1a cause DYT1 dystonia, a neurodevelopmental movement disorder characterized by involuntary sustained twisting movements. Homozygous Tet(TorA) mice are perinatal lethal, while heterozygotes are viable and fertile. Expression of torsinA requires the Cre recombinase-mediated excision of the floxed STOP cassette. In this configuration, torsinA is expressed in cre expressing cells of the offspring. The expression of a tetracycline-controlled suppressor protein (tTS) creates a dox regulatable torsinA expressing line. With dox administration, mice express normal levels of torsinA. Removal of dox results in the repression of torsinA expression due to the binding of the tTS to the tetO promoter. Suppression of torsinA expression during embryogenesis caused dystonia-mimicking behavioral and neuropathological phenotypes. Suppression of torsinA expression during adulthood elicits no abnormalities, establishing an essential requirement for torsinA during a developmental critical period. Of note, tTS expression is not required for this strain to function properly, the approach was used to efficiently repress (and de-repress) transcription for specific experiments. The line functions as a normal floxed-STOP strain when tTS is not present. The addition of other exogenous tetracycline responsive transcriptional elements provides further temporal control of Tor1a expression.

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CRISPR/Extreme Genome Editing technology was used to develop Tet(TorA) mice, which have a loxP-flanked STOP cassette followed by the tetracycline operator (tetO) inserted upstream of the start codon of the endogenous Tor1a gene. Expression of torsinA requires the Cre recombinase-mediated excision of the floxed STOP cassette. This mutant mouse strain may be useful for enabling spatiotemporal control of the endogenous torsinA allele and for studying its role in DYT1 dystonia pathogenesis and therapeutics.

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