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Department of Genetics and Development, College of Physicians and Surgeons, Columbia University, New York, NY 10032

Address correspondence to Frank Costantini, College of Physicians and Surgeons, Columbia University, 701 W. 68th St., New York, NY 10032. Tel.: (212) 305-6814. Fax: (212) 923-2090. E-mail: fdc3{at}columbia.edu

Axin is a component of the canonical Wnt pathway that negatively regulates signal transduction by promoting degradation of ß-catenin. To study the role of Axin in development, we developed strains of transgenic mice in which its expression can be manipulated by the administration of doxycycline (Dox). Animals carrying both mouse mammary tumor virus (MMTV)–reverse tetracycline transactivator and tetracycline response element (TRE)2–Axin–green fluorescent protein (GFP) transgenes exhibited Dox-dependent Axin expression and, when induced from birth, displayed abnormalities in the development of mammary glands and lymphoid tissues, both sites in which the MMTV promoter is active. The transgenic mammary glands underwent normal ductal elongation and side branching during sexual maturation and early pregnancy, but failed to develop lobulo-alveoli, resulting in a defect in lactation. Axin attenuated the expression of cyclin D1, a Wnt target that promotes the growth and differentiation of mammary lobulo-alveoli. Increased apoptosis occurred in the mammary epithelia, consistent with the inhibition of a Wnt/cyclin D1 survival signal by Axin. High levels of programmed cell death also occurred in the thymus and spleen. Immature thymocytes underwent massive apoptosis, indicating that the overexpression of Axin blocks the normal development of T lymphocytes. Our data imply that the Axin tumor suppressor controls cell survival, growth, and differentiation through the regulation of an apoptotic signaling pathway.

Key Words: Axin; Wnt signaling; cyclin D1; apoptosis; developmental abnormalities

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