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2007 Scientific Report

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  • Michigan
  • Molecular

VARI |

VARI | 2007 Research Interests Our laboratory is interested in understanding how alterations in the Wnt signaling pathway cause human disease. Specifically, we have focused our efforts on the functions of the Wnt co-receptors, Lrp5 and Lrp6. Wnt signaling is an evolutionarily conserved process that functions in the differentiation of most tissues within the body. Given its central role in growth and differentiation, it is not surprising that alterations in the pathway are among the most common events associated with human cancer. In addition, several other human diseases, including osteoporosis, have been linked to altered regulation of this pathway. We also work on understanding the role of Wnt signaling in bone formation. Our interest is not only from the perspective of normal bone development, but also in trying to understand whether aberrant Wnt signaling plays a role in the predisposition of some common tumor types (for example, prostate, breast, lung, and renal tumors) to metastasize to and grow in bone. The long-term goal of this work is to provide insights that could be used in developing strategies to lessen the morbidity and mortality associated with skeletal metastasis. Wnt signaling in normal bone development 79 Mutations in the Wnt receptor, Lrp5, have been causally linked to alterations in human bone development. We have characterized a mouse strain deficient for Lrp5 and shown that it recapitulates the low-bone-density phenotype seen in human patients deficient for Lrp5. We have furthered this study by showing that mice carrying mutations in both Lrp5 and the related Lrp6 protein have even more-severe defects in bone density. To test whether Lrp5 deficiency causes changes in bone density due to aberrant signaling through β-catenin, we created mice carrying an osteoblast-specific deletion of β-catenin (OC-cre;β-catenin-flox/flox mice). In collaboration with Tom Clemens of the University of Alabama at Birmingham, we found that alterations in Wnt/β-catenin signaling in osteoblasts lead to changes in the expression of RANKL and osteoprotegerin (OPG). Consistent with this, histomorphometric evaluation of bone in the mice with osteoblast-specific deletions of either Apc or β-catenin revealed significant alterations in osteoclastogenesis. We are currently addressing how other genetic alterations linked to Wnt/β-catenin signaling affect bone development and osteoblast function. We have generated mice with a conditional allele of Lrp6 that can be inactivated via cre-mediated recombination, and we will assess the role of Lrp6 in terminal osteoblast differentiation. We are also generating mice carrying a conditional deletion of Lrp5 in differentiated osteoblasts, and we will characterize their phenotype. Finally, we are working to determine what other signaling pathways in osteoblasts may impinge on β-catenin signaling to control osteoblast differentiation and function. General mechanisms of Wnt signaling There are many levels of regulating the reception of Wnt signals. The completion of the Human Genome Project has shown that there are 19 different genes encoding Wnt proteins, 9 encoding Frizzled proteins, and the genes encoding Lrp5 and Lrp6. In addition, there are several proteins that can inhibit Wnt signaling by binding to components of the receptor complex and interfering with normal signaling, including the Dickkopfs (Dkks) and the Frizzled-related proteins (FRPs). One of the long-term goals of our laboratory is to understand how specificity is generated for the different signaling pathways, with a specific focus on understanding the molecular functions of Lrp5 and Lrp6.

Van Andel Research Institute | Scientific Report Wnt signaling in prostate development and cancer Two hallmarks of advanced prostate cancer are the development of skeletal osteoblastic metastasis and the ability of the tumor cells to become independent of androgen for survival. The association of Wnt signaling with bone growth, plus the fact that β-catenin can bind to the androgen receptor and make it more susceptible to activation with steroid hormones other than DHT, make Wnt signaling an attractive candidate for explaining some phenotypes associated with advanced prostate cancer. We have created mice with a prostate-specific deletion of the Apc gene. These mice develop fully penetrant prostate hyperplasia by four months of age, and these tumors progress to frank carcinomas by seven months. We have found that these tumors initially regress under androgen ablation but show signs of androgen-independent growth some months later. Wnt signaling in mammary development and cancer We are also addressing the relative roles of Lrp5 and Lrp6 in Wnt1-induced mammary carcinogenesis. A deficiency in Lrp5 dramatically inhibits the development of mammary tumors in this context. A germline deficiency for Lrp5 or Lrp6 results in delayed mammary development. As Lrp5-deficient mice are viable and fertile, we have focused our initial efforts on these mice. In collaboration with Caroline Alexander’s laboratory, we have found dramatic reductions in the number of mammary progenitor cells in these mice. We are continuing to examine the mechanisms underlying this reduction. 80 VARI mutant mouse repository With support from the Van Andel Institute, my laboratory maintains a repository of mutant mouse strains to support the general development of animal models of human disease. We distribute these strains at a nominal cost to interested laboratories. External Collaborators Bone development Mary Bouxsein, Beth Israel Deaconness Medical Center, Boston, Massachusetts Thomas Clemens, University of Alabama–Birmingham Marie Claude Faugere, University of Kentucky, Lexington David Ornitz and Fanxin Long, Washington University, St. Louis, Missouri Matthew Warman, Harvard University, Boston, Massachusetts Prostate cancer Wade Bushman and Ruth Sullivan, University of Wisconsin–Madison Mammary development Caroline Alexander, University of Wisconsin–Madison Yi Li, Baylor Breast Center, Houston, Texas Jeffrey Rubin, National Cancer Institute, Bethesda, Maryland Mechanisms of Wnt signaling Kathleen Cho, University of Michigan, Ann Arbor Kang-Yell Choi, Yansei University, Seoul, South Korea Eric Fearon, University of Michigan, Ann Arbor Silvio Gutkind, National Institute of Dental and Craniofacial Research, Bethesda, Maryland Kun-Liang Guan, University of Michigan, Ann Arbor

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