Biomedical Engineering Reference
In-Depth Information
expressed throughout development and in the adult. Studies of mice with disruption of
a single
gene have revealed phenotypes that range from defective social behavior to
developmental defects that include abnormal heart, skeletal, and cochlear morphogen-
esis, suggesting that each of the Dvl genes had unique functions. However, analysis of
double or triple Dvl knock-outs revealed novel phenotypes or more severe phenotypes
displayed by single knock-outs suggesting overlapping or redundant functions of these
Dvl genes. Most if not all of the phenotypes displayed by the Dvl mutants appear to be
the result of PCP pathway functions, not of the canonical Wnt pathway. This suggests
that the PCP pathway is sensitive to reduction of
Dvl
Dvls
, but only one
Dvl
allele of six may
be required for Wnt pathway.
The well-conserved canonical and noncanonical Wnt pathways are impor-
tant for all aspects of mammalian development (
Wang, Etheridge, &
Wynshaw-Boris, 2006
), and various human diseases, including develop-
mental diseases and cancer, are caused by abnormal Wnt signaling. Signals
from extracellular Wnt ligands are received by three classes of coreceptors.
These signals are interpreted and transduced to the nucleus and/or cytoskel-
eton via a number of intracellular proteins, including Dishevelleds (Dvls).
Depending on whether the pathways result in
-catenin-mediated gene
transcription, we can divide the multiple Wnt pathways into canonical
(
b
-catenin-independent) Wnt
pathways. Activation of the canonical Wnt pathway results in the stabiliza-
tion of
b
-catenin-dependent) and noncanonical
(
b
-catenin to alter transcriptional activity in the nucleus, while acti-
vation of the Wnt/planar cell polarity (Wnt/PCP) pathway, a noncanonical
Wnt pathway, results in changes in epithelial polarity and tissue reorganiza-
tion by modulating cytoskeletal organization and adhesion. Understanding
how the various Wnt pathways that regulate development are integrated
in
vivo
is an important outstanding question. Dvls are outstanding candidates to
address this question, as these conserved proteins are required in all eukary-
otes for both canonical and noncanonical Wnt pathways.
Over the past 15 years, our laboratory has produced null alleles of each of
the three
Dvl
genes in mice, and we have used these mice to uncover par-
tially unique but predominantly redundant functions among the three
Dvl
genes. In support of unique functions for each of the Dvls, single mutants
for
Dvl1
display novel social behavior abnormalities (
Lijam et al., 1997
),
while both
Dvl2
(
Hamblet et al., 2002
) and
Dvl3
(
Etheridge et al., 2008
)
mutants die at birth conotruncal heart defects and display cochlear abnor-
malities.
Dvl1
;
Dvl2
(
Wang, Hamblet, et al., 2006; Wang et al., 2005
) and
Dvl2
;
Dvl3
double mutants (
Etheridge et al., 2008
) display severe neural
tube defects (craniorachischisis) and severe cochlear defects, while
Dvl1
;
b
