A Mouse Transgenic Approach To Induce Beta-Catenin Signaling In A Temporally Controlled Manner

Although constitutive murine transgenic models have provided important insights into beta-catenin signaling in tissue morphogenesis and tumorigenesis, these models are unable to express activated beta-catenin in a temporally controlled manner. Therefore, to enable the induction (and subsequent de-induction) of beta-catenin signaling during a predetermined time-period or developmental stage, we have generated and characterized a TETO-Delta N89 beta-catenin responder transgenic mouse. Crossed with the MTB transgenic effector mouse, which targets the expression of the reverse tetracycline transactivator (rtTA) to the mammary epithelium, we demonstrate that the stabilized (and activated) form of beta-catenin (Delta N89 beta-catenin) is expressed only in the presence doxycycline-activated rtTA in the mammary epithelial compartment. Furthermore, we show that transgene-derived Delta N89 beta-catenin elicits significant mammary epithelial proliferation and precocious alveologenesis in the virgin doxycycline-treated MTB/TETO-Delta N89 beta-catenin bitransgenic. Remarkably, deinduction of TETO-Delta N89 beta-catenin transgene expression (through doxycycline withdrawal) results in the reversal of these morphological changes. Importantly, continued activation of the TETO-Delta N89 beta-catenin transgene results in palpable mammary tumors (within 7-9 months) in the doxycycline-treated virgin MTB/TETO-Delta N89 beta-catenin bigenic but not in the same bitransgenic without doxycycline administration. Collectively, these mammary epithelial responses to Delta N89 beta-catenin expression agree with previous reports using conventional transgenesis and therefore confirm that Delta N89 beta-catenin functions as expected in this doxycycline-responsive bigenic system. In sum, our mammary gland studies demonstrate "proof-of-principle" for using the TETO-Delta N89 beta-catenin transgenic responder to activate (and then de-activate) beta-catenin signaling in any tissue of interest in a spatiotemporal specific fashion.