2016 Scientific Report
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BART O. WILLIAMS, PH.D.<br />
Dr. Williams received his Ph.D. in biology from Massachusetts Institute<br />
of Technology in 1996, where he trained with Tyler Jacks. Following<br />
his postdoctoral study with Harold Varmus, Dr. Williams joined VARI as<br />
a <strong>Scientific</strong> Investigator in July 1999. He is now a Professor and the<br />
Director of the Center for Cancer and Cell Biology.<br />
STAFF<br />
CASSIE DIEGEL, B.S.<br />
NICOLE ETHEN, B.S.<br />
DIANA LEWIS, A.S.<br />
MITCH MCDONALD, B.S.<br />
ALEX ZHONG, PH.D.<br />
STUDENTS<br />
CHERYL CHRISTIE, B.S.<br />
CASEY DROSCHA, B.S.<br />
JOHAN LEE<br />
JON LENSING<br />
KEVIN MAUPIN, B.A., B.S.<br />
AGNI NAIDU, B.S.<br />
RESEARCH INTERESTS<br />
Our laboratory is interested in understanding how alterations in the Wnt signaling<br />
pathway cause human disease. Wnt signaling is a process, conserved throughout<br />
evolution, that functions in the differentiation of most tissues. Given its central role<br />
in growth and differentiation, it is not surprising that alterations in the Wnt pathway<br />
are among the most common events associated with human cancer. In addition,<br />
other human diseases including osteoporosis, cardiovascular disease, and diabetes<br />
have been linked to altered regulation of this pathway. A specific focus of our work is<br />
characterizing the role of Wnt signaling in bone formation. Our interest is not only in<br />
normal bone development but also in understanding whether aberrant Wnt signaling<br />
plays a role in the metastasis of some common cancers (for example, prostate, breast,<br />
lung, and renal tumors) to the bone. The long-term goal of this work is to provide<br />
insights useful in developing strategies to lessen the morbidity and mortality associated<br />
with skeletal metastasis.<br />
Wnt signaling in normal bone development<br />
Mutations in Lrp5, a Wnt receptor, have been causally linked to alterations in human<br />
bone development. We have characterized a mouse strain deficient in Lrp5 and have<br />
shown that it recapitulates the low-bone-density phenotype seen in human patients<br />
who have that deficiency. We have further shown that mice carrying mutations in both<br />
Lrp5 and the related Lrp6 protein have even more-severe defects in bone density. To<br />
test whether Lrp5 deficiency causes changes in bone density due to aberrant signaling<br />
through β-catenin, we created OC-Cre;β-catenin flox/flox mice, which carry an osteoblastspecific<br />
deletion of β-catenin. We are addressing how other genetic alterations linked<br />
to Wnt/β-catenin signaling affect bone development and osteoblast function. We have<br />
generated mice with conditional alleles of Lrp6 and Lrp5 that can be inactivated via<br />
Cre-mediated recombination and have used them to show that both Lrp5 and Lrp6<br />
function within osteoblasts to regulate normal bone development and homeostasis. We<br />
have also created mice lacking the ability to secrete Wnts from osteoblasts and shown<br />
that these mice have extremely low bone mass, establishing that the mature osteoblast<br />
is an important source of Wnts.<br />
24 Van Andel Research Institute | <strong>Scientific</strong> <strong>Report</strong>