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doi: 10.1242/10.1242/jcs.00334
Research Article |
1 Program in Developmental Biology, Baylor College of Medicine, Houston, TX
77030, USA
2 Department of Biochemistry and Molecular Biology, University of Texas M.D.
Anderson Cancer Center, Houston, TX 77030, USA
3 Department of Molecular and Cellular Biology, Baylor College of Medicine,
Houston, TX 77030, USA
* Author for correspondence (e-mail: jrosen{at}bcm.tmc.edu)
Accepted 23 December 2002
The Wnt (wingless) family of secreted glycoproteins initiates a signalling pathway implicated in the regulation of both normal mouse mammary gland development and tumorigenesis. Multiple Wnt signals ultimately converge on the multifunctional protein ß-catenin to activate the transcription of target genes. Although ß-catenin plays a crucial role in canonical Wnt signalling, it also functions in epithelial cell-cell adhesion at the adherens junctions. This study was designed to isolate ß-catenin's signalling function from its role in adherence during mouse mammary gland development. A transgenic dominant-negative ß-catenin chimera (ß-eng), which retains normal protein-binding properties of wild-type ß-catenin but lacks its C-terminal signalling domain, was expressed preferentially in the mammary gland. Thus, ß-eng inhibits the signalling capacity of endogenous ß-catenin, while preserving normal cell-cell adhesion properties. Analysis of the mammary gland in transgenic mice revealed a severe inhibition of lobuloalveolar development and a failure of the mice to nurse their young. Expression of ß-eng resulted in an induction of apoptosis both in transgenic mice and in retrovirally transduced HC11 cells. Thus, endogenous ß-catenin expression appears to be required to provide a survival signal in mammary epithelial cells, which can be suppressed by transgenic expression of ß-eng. Comparison of the timing of transgene expression with the transgenic phenotype suggested a model in which ß-catenin's survival signal is required in lobular progenitors that later differentiate into lobuloalveolar clusters. This study illustrates the importance of ß-catenin signalling in mammary lobuloalveolar development.
Key words: ß-catenin, Wnt, Mammary gland, Apoptosis, Lobular
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