A mouse transgenic approach to induce β-catenin signaling in a temporally controlled manner.
Although constitutive murine transgenic models have provided important insights into β-catenin signaling in tissue morphogenesis and tumorigenesis, these models are unable to express activated β-catenin in a temporally controlled manner. Therefore, to enable the induction (and subsequent de-induction) of β-catenin signaling during a predetermined time-period or developmental stage, we have generated and characterized a TETO-ΔN89β-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 β-catenin (ΔN89β-catenin) is expressed only in the presence doxycycline-activated rtTA in the mammary epithelial compartment. Furthermore, we show that transgene-derived ΔN89β-catenin elicits significant mammary epithelial proliferation and precocious alveologenesis in the virgin doxycycline-treated MTB/TETO-ΔN89β-catenin bitransgenic. Remarkably, deinduction of TETO-ΔN89β-catenin transgene expression (through doxycycline withdrawal) results in the reversal of these morphological changes. Importantly, continued activation of the TETO-ΔN89β-catenin transgene results in palpable mammary tumors (within 7-9 months) in the doxycycline-treated virgin MTB/TETO-ΔN89β-catenin bigenic but not in the same bitransgenic without doxycycline administration. Collectively, these mammary epithelial responses to ΔN89β-catenin expression agree with previous reports using conventional transgenesis and therefore confirm that ΔN89β-catenin functions as expected in this doxycycline-responsive bigenic system. In sum, our mammary gland studies demonstrate "proof-of-principle" for using the TETO-ΔN89β-catenin transgenic responder to activate (and then de-activate) β-catenin signaling in any tissue of interest in a spatiotemporal specific fashion.
Department of Molecular and Cellular Biology, Room M733A, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Atish
A
Mukherjee
Selma M
SM
Soyal
Jie
J
Li
Yan
Y
Ying
Maria M
MM
Szwarc
Bin
B
He
Ramakrishna
R
Kommagani
Myles C
MC
Hodgson
Minoti
M
Hiremath
Pamela
P
Cowin
John P
JP
Lydon
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004318:Doxycycline / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D008321:Mammary Glands, Animal / Q000196:embryology* / Q000378:metabolism; D015674:Mammary Neoplasms, Animal / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009024:Morphogenesis; D015398:Signal Transduction; D051176:beta Catenin / Q000096:biosynthesis* / Q000235:genetics
D051176:beta Catenin; D004318:Doxycycline