Biomedical Engineering Reference
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Dvl3 double mutants die during midgestation ( Etheridge et al., 2008 ). Loss
of five of six Dvl alleles results in defects in nodal cilia posterior localization
and left-right asymmetry defects ( Hashimoto et al., 2010 ). In further support
of redundancy, Dvl1 ; Dvl2 ; Dvl3 triple homozygous mutants are unable to
undergo gastrulation and do not form mesoderm (unpublished results from
our lab and the lab of Hiroshi Hamada). We have begun to dissect the in
vivo pathways that Dvls regulate normal development and are disrupted in
the Dvl mutants to produce these phenotypes. Taking advantage of studies
in Drosophila and Xenopus that identified domains in Dvl proteins required
for either canonical Wnt or noncanonical Wnt/PCP pathway function, we
produced in vivo allelesinmicethatcandistinguishthesetwopathways.We
used these alleles to provide definitive evidence that the craniorachischisis
phenotype displayed by Dvl1 ; Dvl2 double mutants resulted from disruption
of convergent extension movements via the Wnt/PCP pathway.
In this review, I highlight these in vivo studies of Dvl function in mice.
I briefly discuss the major Wnt pathways. Then, as most if not all of the iden-
tified phenotypes appear to be the result of defective noncanonical Wnt/
PCP signaling, and this volume focuses on the PCP pathway, I focus on
these functions of Dvl in mammals.
1. CANONICAL Wnt PATHWAY
In the absence of Wnt signal, glycogen synthase kinase-3 (Gsk3) is ac-
tive and phosphorylates
b
-catenin. This results in the ubiquitination and
degradation of
-catenin through the proteosome pathway. Transcription
factors of the TCF/LEF family are associated with corepressors in the nu-
cleus to repress transcription of genes containing response elements for these
transcription factors. In the presence of Wnt, a secreted protein associated
with the extracellular matrix (ECM), the Wnt ligand binds to its receptor
Fz and coreceptors Lrp5/6 and activates Dishevelled (Dvl in mice, Dsh in
flies). Dvl/Dsh activation leads to the inactivation of Gsk3 as part of a large
multiprotein complex including axin,
b
b
-catenin and APC, the product of
the gene mutated in the human disorder adenomatous polyposis coli. As
a result, b -catenin is stabilized and binds to TCF/LEF. b -Catenin binding
dismisses the associated corepressors from TCF and LEFs and activates tran-
scription of genes containing response elements for these transcription fac-
tors. Thus, the result of Wnt signaling is to convert extracellular signals into
changes in transcriptional activity. Many of the murine homologues of this
pathway are expressed throughout development, and the canonical Wnt
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