Wnt-10b directs hypermorphic development and transformation in mammary glands of male and female mice

Lane, Timothy F.; Leder, Philip

doi:10.1038/sj.onc.1201593

Cited by 135 publications

(115 citation statements)

References 18 publications

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“…Consistent with this idea, transgenic mice that express elevated Wnt10b from the mouse mammary tumor virus promoter show developmental alterations in the mammary gland, including expanded glandular development and precocious appearance of alveoli in virgin females (38). Expression of Wnt10b from the FABP4 promoter results in a different phenotype, with greatly impaired development of mammary glands (data not shown).…”

Section: Discussionsupporting

confidence: 60%

Wnt10b Inhibits Development of White and Brown Adipose Tissues

Longo¹,

Wright²,

Kang³

et al. 2004

Journal of Biological Chemistry

339

298

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Wnt is a family of secreted signaling proteins that regulate diverse developmental processes. Activation of canonical Wnt signaling by Wnt10b inhibits differentiation of preadipocytes in vitro. To determine whether Wnt signaling blocks adipogenesis in vivo, we created transgenic mice in which Wnt10b is expressed from the FABP4 promoter. Expression of Wnt10b in adipose impairs development of this tissue throughout the body, with a decline of ϳ50% in total body fat and a reduction of ϳ60% in weight of epididymal and perirenal depots. FABP4-Wnt10b mice resist accumulation of adipose tissue when fed a high fat diet. Furthermore, transgenic mice are more glucose-tolerant and insulin-sensitive than wild type mice. Expression of Wnt10b from the FABP4 promoter also blocks development of brown adipose tissue. Interscapular tissue of FABP4-Wnt10b mice has the visual appearance of white adipose tissue but expresses neither brown (e.g. uncoupling protein 1) nor white adipocyte markers. Transgenic mice are unable to maintain a core body temperature when placed in a cold environment, providing further evidence that Wnt10b inhibits development of brown adipose tissue. Although food intake is not altered in FABP4-Wnt10b mice, oxygen consumption is decreased. Thus, FABP4-Wnt10b mice on a chow diet gain more weight than controls, largely because of an increase in weight of skin. In summary, inhibition by Wnt10b of white and brown adipose tissue development results in lean mice without lipodystrophic diabetes.The program followed by preadipocytes as they differentiate into adipocytes has been well characterized (1-3). Activation of a cascade of transcription factors, including PPAR␥ 1 and members of the C/EBP family, results in global changes in gene expression that cause the loss of preadipocyte characteristics and the acquisition of the adipocyte phenotype. Whether preadipocytes remain quiescent, divide, or differentiate is influenced by both inhibitory and stimulatory factors (4). One of the endogenous factors proposed to repress adipogenesis is Wnt10b, which belongs to a large family of secreted, cysteine-rich proteins that regulate diverse cellular processes, including development. Although Wnt regulates cell fate through several signaling pathways (5, 6), activation of the canonical Wnt/␤-catenin pathway is sufficient to inhibit differentiation and apoptosis of preadipocytes (7-11). A model for the canonical signaling pathway has arisen from extensive genetic and biochemical studies. In the absence of Wnt, glycogen synthase kinase-3 phosphorylates ␤-catenin, which targets this protein for ubiquitin-mediated degradation by the proteasome. In the presence of Wnt, activation of Frizzled receptors and low density lipoprotein receptor-related protein coreceptors disrupts the complex of proteins that contain glycogen synthase kinase-3 and ␤-catenin. Hypophosphorylated ␤-catenin then accumulates in the cytosol, translocates to the nucleus, and binds to T-cell factor/lymphoid-enhancing factor transcription factors to mediate the eff...

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Section: Discussionsupporting

confidence: 60%

Wnt10b Inhibits Development of White and Brown Adipose Tissues

Longo¹,

Wright²,

Kang³

et al. 2004

Journal of Biological Chemistry

339

298

View full text Add to dashboard Cite

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“…Thus, Lef1 and Wnt10b are the likely transcription factor and ligand, respectively, mediating Wnt/␤-catenin signaling during fungiform papillae formation. Although Wnt10b has not been well characterized biochemically, there are several examples demonstrating Wnt10b's function as a ligand for the Wnt/␤-catenin signaling pathway (27)(28)(29)(30). In addition, we have confirmed that Wnt10b induces double axis formation when expressed in Xenopus embryos (K.I.…”

Section: Discussionsupporting

confidence: 57%

Wnt signaling interacts with Shh to regulate taste papilla development

Iwatsuki

Liu

Grónder

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

146

208

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“…Generation of Transgenic Mice-The human COX-2 gene (23) was cloned behind the murine mammary tumor virus (MMTV) promoter (24). The linearized construct was used to derive transgenic CD1 mice (Charles River Laboratories) in the UCHC transgenic core facility.…”

Section: Methodsmentioning

confidence: 99%

“…Whole Mount, Histological Methods, and ImmunohistochemistryMammary glands were dissected and processed for whole mount analysis as described (24,26). Some glands were fixed and analyzed by histological methods (28).…”

Section: Methodsmentioning

confidence: 99%

Overexpression of Cyclooxygenase-2 Is Sufficient to Induce Tumorigenesis in Transgenic Mice

Liu

Chang

Narko

et al. 2001

Journal of Biological Chemistry

729

471

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The cyclooxygenase (COX)-2 gene encodes an inducible prostaglandin synthase enzyme that is overexpressed in adenocarcinomas and other tumors. Deletion of the murine Cox-2 gene in Min mice reduced the incidence of intestinal tumors, suggesting that it is required for tumorigenesis. However, it is not known if overexpression of Cox-2 is sufficient to induce tumorigenic transformation. We have derived transgenic mice that overexpress the human COX-2 gene in the mammary glands using the murine mammary tumor virus promoter. The human Cox-2 mRNA and protein are expressed in mammary glands of female transgenic mice and were strongly induced during pregnancy and lactation. Female virgin Cox-2 transgenic mice showed precocious lobuloalveolar differentiation and enhanced expression of the ␤-casein gene, which was inhibited by the Cox inhibitor indomethacin. Mammary gland involution was delayed in Cox-2 transgenic mice with a decrease in apoptotic index of mammary epithelial cells. Multiparous but not virgin females exhibited a greatly exaggerated incidence of focal mammary gland hyperplasia, dysplasia, and transformation into metastatic tumors. Cox-2-induced tumor tissue expressed reduced levels of the proapoptotic proteins Bax and Bcl-x L and an increase in the anti-apoptotic protein Bcl-2, suggesting that decreased apoptosis of mammary epithelial cells contributes to tumorigenesis. These data indicate that enhanced Cox-2 expression is sufficient to induce mammary gland tumorigenesis. Therefore, inhibition of Cox-2 may represent a mechanism-based chemopreventive approach for carcinogenesis.

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Wnt-10b directs hypermorphic development and transformation in mammary glands of male and female mice

Cited by 135 publications

References 18 publications

Wnt10b Inhibits Development of White and Brown Adipose Tissues

Wnt10b Inhibits Development of White and Brown Adipose Tissues

Wnt signaling interacts with Shh to regulate taste papilla development

Overexpression of Cyclooxygenase-2 Is Sufficient to Induce Tumorigenesis in Transgenic Mice

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