A beta-catenin survival signal is required for normal lobular development in the mammary gland.
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 beta-catenin to activate the transcription of target genes. Although beta-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 beta-catenin's signalling function from its role in adherence during mouse mammary gland development. A transgenic dominant-negative beta-catenin chimera (beta-eng), which retains normal protein-binding properties of wild-type beta-catenin but lacks its C-terminal signalling domain, was expressed preferentially in the mammary gland. Thus, beta-eng inhibits the signalling capacity of endogenous beta-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 beta-eng resulted in an induction of apoptosis both in transgenic mice and in retrovirally transduced HC11 cells. Thus, endogenous beta-catenin expression appears to be required to provide a survival signal in mammary epithelial cells, which can be suppressed by transgenic expression of beta-eng. Comparison of the timing of transgene expression with the transgenic phenotype suggested a model in which beta-catenin's survival signal is required in lobular progenitors that later differentiate into lobuloalveolar clusters. This study illustrates the importance of beta-catenin signalling in mammary lobuloalveolar development.
Tepera
Stacey B
SB
Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA.
McCrea
Pierre D
PD
Rosen
Jeffrey M
JM
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D008321:Mammary Glands, Animal / Q000166:cytology / Q000254:growth & development* / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism*; D051176:beta Catenin
C495267:CTNNB1 protein, mouse; C495268:Ctnnb1 protein, rat; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin