Impaired mammary gland and lymphoid development caused by inducible expression of Axin in transgenic mice

doi:10.1083/jcb.200107066

Published 10 December 2001. doi:10.1083/jcb.200107066

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© The Rockefeller University Press, 0021-9525/2001/12/1055 $5.00
The Journal of Cell Biology, Volume 155, Number 6, December 10, 2001 1055-1064

Article

Impaired mammary gland and lymphoid development caused by inducible expression of Axin in transgenic mice

Wei Hsu, Reena Shakya and Frank Costantini

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 negativelyregulates signal transduction by promoting degradation of ß-catenin.To study the role of Axin in development, we developed strainsof transgenic mice in which its expression can be manipulatedby the administration of doxycycline (Dox). Animals carryingboth mouse mammary tumor virus (MMTV)–reverse tetracyclinetransactivator and tetracycline response element (TRE)2–Axin–greenfluorescent protein (GFP) transgenes exhibited Dox-dependentAxin expression and, when induced from birth, displayed abnormalitiesin the development of mammary glands and lymphoid tissues, bothsites in which the MMTV promoter is active. The transgenic mammaryglands underwent normal ductal elongation and side branchingduring sexual maturation and early pregnancy, but failed todevelop lobulo-alveoli, resulting in a defect in lactation.Axin attenuated the expression of cyclin D1, a Wnt target thatpromotes the growth and differentiation of mammary lobulo-alveoli.Increased apoptosis occurred in the mammary epithelia, consistentwith the inhibition of a Wnt/cyclin D1 survival signal by Axin.High levels of programmed cell death also occurred in the thymusand spleen. Immature thymocytes underwent massive apoptosis,indicating that the overexpression of Axin blocks the normaldevelopment of T lymphocytes. Our data imply that the Axin tumorsuppressor controls cell survival, growth, and differentiationthrough the regulation of an apoptotic signaling pathway.

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

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