2016 Scientific Report

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