Biomedical Engineering Reference
In-Depth Information
double mutants display a novel phenotype: shortening of cochlear ducts with
abnormal orientation of the hair cells of the inner ear (
Wang, Hamblet, et al.,
2006; Wang et al., 2005
), a phenotype similar to
Dvl3
single mutants.
Additionally, the skeletal and cardiac abnormalities seen in
Dvl2
mutants
were also more severe in the
Dvl1/2
double mutants than in
Dvl2
single
mutants. The neural tube and cochlear elongation defects result from
convergent extension defects, while the inner ear hair cell defects are due
to defects in polarity of these cells. All of these defects in
Dvl1/2
mutants
result from defective Wnt/PCP pathway (
Wang, Hamblet, et al., 2006
,
see below). We have not determined which of these pathways causes the
somite defects that result in skeletal abnormalities in the
Dvl2
and
Dvl1/2
mutants, and there is evidence for both Wnt and PCP pathway defects to
explain the conotruncal abnormalities (
Kioussi et al., 2002; Zhou et al.,
2007
, see above).
The mammalian auditory sensory organ, the organ of Corti, consists of
precise arrays of sensory hair cells with uniformly oriented stereocilia on the
apical surfaces that display a distinct PCP parallel to the sensory epithelium.
We demonstrated that the mature organ of Corti is formed from a thicker
and shorter postmitotic primordium through unidirectional extension, char-
acteristic of convergent extension (
Wang et al., 2005
). Mutations in the PCP
pathway, including
Lp
and
Dvl1/2
mutants, interfered with this extension,
resulting in the formation of a shortened and widened cochlear duct and
its sensory organ, as well as misorientation of stereocilia. Analogous to the
homologous pathway in
Drosophila
, Dvl2 displays PCP-dependent polar-
ized subcellular localization across the organ of Corti. This study suggests
a conserved underlying molecular mechanism for PCP pathway regula-
tion of polarized extension and PCP of the organ of Corti in invertebrates
and vertebrates and indicates that the mammalian PCP pathway might
directly couple cellular intercalation movements to the establishment of
PCP in the cochlea.
11. DVL1/3 DOUBLE MUTANTS
Normal development was observed in
Dvl1
/
;
Dvl3
/
embryos un-
til E12.5 (
Etheridge et al., 2008
), but these mutants died between E13.5 and
E15.5 of unknown causes. The timing of lethality suggests defective vascular
or cardiac function, but further studies are required to determine the precise
cause of death and the pathway(s) responsible.
