Wnt/β-catenin signaling is necessary for initiation of mammary gland development. Postnatally, Wnt signaling has been implicated in the expansion or survival of mammary stem cells. To distinguish between these roles, we used a temporally controllable doxycycline-inducible bi-transgenic system to ectopically and reversibly express the potent secreted Wnt inhibitor Dickkopf1 (Dkk1) in mammary basal cells during puberty. Dkk1 expression was induced from the onset of puberty, and produced a striking block in ductal elongation and branching that was associated with decreased mitotic activity in the stem cell-rich terminal end buds. Analysis of the (CD29/CD49f)hiCD24+ mammary stem cell population revealed that the percentage of stem cells within the mammary epithelium was unchanged by Dkk1 expression. As the total number of epithelial cells was greatly decreased in Dkk1-expressing mammary glands, these data indicate that expansion/self renewal of mammary stem cells is blocked concomitant with inhibition of ductal expansion, but that a core population of mammary stem cells is maintained. Consistent with this hypothesis, withdrawal of doxycycline mid-way through puberty or during pregnancy produced partial reversal of the block to ductal outgrowth and branching. Our results indicate that Wnt signaling is required at multiple stages of mammary gland development, and regulates expansion, but not survival of mammary stem cells.
Wnt/beta signaling regulates expansion but not survival of mammary stem cells
PICCOLO, STEFANO;
2008
Abstract
Wnt/β-catenin signaling is necessary for initiation of mammary gland development. Postnatally, Wnt signaling has been implicated in the expansion or survival of mammary stem cells. To distinguish between these roles, we used a temporally controllable doxycycline-inducible bi-transgenic system to ectopically and reversibly express the potent secreted Wnt inhibitor Dickkopf1 (Dkk1) in mammary basal cells during puberty. Dkk1 expression was induced from the onset of puberty, and produced a striking block in ductal elongation and branching that was associated with decreased mitotic activity in the stem cell-rich terminal end buds. Analysis of the (CD29/CD49f)hiCD24+ mammary stem cell population revealed that the percentage of stem cells within the mammary epithelium was unchanged by Dkk1 expression. As the total number of epithelial cells was greatly decreased in Dkk1-expressing mammary glands, these data indicate that expansion/self renewal of mammary stem cells is blocked concomitant with inhibition of ductal expansion, but that a core population of mammary stem cells is maintained. Consistent with this hypothesis, withdrawal of doxycycline mid-way through puberty or during pregnancy produced partial reversal of the block to ductal outgrowth and branching. Our results indicate that Wnt signaling is required at multiple stages of mammary gland development, and regulates expansion, but not survival of mammary stem cells.
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