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 useful in developing strategies to lessen the morbidity and mortality associated with skeletal metastasis.
Wnt signaling in normal bone development
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 further shown 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 of Wnt/b-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 addressing how other genetic alterations linked to Wnt/b-catenin signaling affect bone development and osteoblast function. We have generated mice with conditional alleles of Lrp6 and Lrp5 that can be inactivated via cre-mediated recombination, and we will assess the roles of these genes at different stages of osteoblast differentiation. Finally, we are working to determine what other signaling pathways may impinge on b-catenin signaling to control osteoblast differentiation and function.
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, and a germline deficiency for Lrp5 or Lrp6 results in delayed mammary development. Because 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, and we are examining the mechanisms underlying this reduction. We have also found that Lrp6 plays a key role in mammary development, and we are focusing on the mechanisms underlying this unique role. Finally, we are defining the relative roles of β-catenin and mTOR signaling in the initiation and progression of Wnt1-induced mammary tumors. We are particularly interested in the role(s) of these pathways in regulating the proliferation of normal mammary progenitor cells, as well as of tumor-initiating cells.
Wnt signaling in metabolic syndrome
Several studies have linked mutations in Lrp5 and/or Lrp6 to the development of diabetes, dyslipedemias, and hypertension in humans and mice. We are exploring the roles of these genes in this context by creating mice carrying conditional deletions in hepatocytes or in adipocytes and evaluating their phenotypes.
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 b-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.
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.
VARI mutant mouse repository
With support from the Institute, our 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
- 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
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 California, San Diego
- Malathy Shekhar, Wayne State University, Detroit, Michigan
- Aaron Zorn, University of Cincinnati
