Reversible gene inactivation in the mouse.

Gene-inactivation techniques in the mouse have become an essential tool for modern biomedical research. Both ubiquitous and tissue-specific inactivation are possible with current approaches, and recent developments facilitate a temporal control of the inactivation process. However, one of the limitations of current procedures is that inactivation is irreversible. We have produced complete and reversible inactivation of the Hoxa2 gene in the mouse using the control elements of the tetracycline-resistance operon. We show that a Hoxa2 allele containing tetracycline operator (tetO) sequences is susceptible to controlled regulation by tTS, a chimeric molecule containing the tetracycline repressor and a transcriptional repressing domain. This inhibition was specific to the tetO-modified allele, did not affect neighboring genes, and was reversible by administration of doxycycline to the pregnant female. This procedure allows the production of gene inactivation that is complete, is reversible, and can be controlled at the spatial and temporal levels.