Biomedical Engineering Reference
In-Depth Information
17. CONCLUSIONS AND FUTURE STUDIES
The phenotypes of single
Dvl
mutants (
Fig. 9.1
) reveal unique func-
tions of each of the
Dvl
genes, but the phenotypes of double and triple
Dvl
mutants (
Fig. 9.1
) also reveal a high level of functional redundancy among
this gene family. The level of redundancy is not surprising, given that all
three
Dvl
genes are highly conserved and broadly expressed during develop-
ment and in the adult. Why are there unique phenotypes? There may be
some situations where one of the
Dvls
has predominant expression pattern.
For example,
Dvl1
may play some unique role in the brain, based on the
singular behavioral phenotype displayed by the
Dvl1
mutants.
Dvl2
and
Dvl3
may have higher levels of expression in the developing heart, which
could explain the conotruncal defects displayed by these mutants.
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.
Clearly, the neurulation, cochlear elongation, cochlear hair cell polarity,
nodal cilia polarity, and axonal guidance phenotypes are the result of
PCP pathway functions. There is evidence that the brain defects that could
explain the
Dvl1
behavioral deficits are due to PCP pathway functions. The
pathway dependence of the skeletal and severe gastrulation defects is not
currently known. We will attempt to employ the
Dvl2
allelic series to test
these phenotypes
in vivo
, based on the functional redundancy of the
Dvls in
vivo
. However, this may not be successful, and allelic series for
Dvl1
and/or
Dvl3
may have to be produced and tested. It will also be helpful if down-
stream targets of the PCP pathway can be identified.
What is perhaps most interesting and surprising is that there are no clear
canonical Wnt pathway defects yet identified in the
Dvl
mutants. This suggests
that the PCP pathway is sensitive to reduction of
Dvls
, but only one
Dvl
allele
of six may be required for Wnt pathway. Why? There may be unique as well
as redundant
Dvl
functions in the PCP pathway, but the function of each of
the Dvls is only redundant in the Wnt pathway, and a single
Dvl
allele may be
sufficient for Wnt signaling necessary for grossly normal development.
Several of these and other unanswered questions may be approachable by
the use of conditional
Dvl
alleles. Each of the fluorescently tagged BAC
transgenic alleles is also conditional alleles and can be used for studying
the redundancy and pathway dependence of
Dvl
function, and to examine
later phenotypes that may be revealed when earlier embryonic lethal phe-
notypes are circumvented.