Biomedical Engineering Reference
In-Depth Information
of stereociliary bundles. These include
Crsh
and
Scy
(
Crash
and
Spin
)
cycle
,
two distinct mutations of
Celsr1
, a homologue of the PCP pathway
member
flamingo
(
Curtin et al., 2003
),
Fz3
/
;
Fz6
/
(
Wang, Guo, &
Nathans, 2006
), and
Dvl1
/
;
Dvl2
/
(
Wang et al., 2005
) mutants (see
below). Vangl2 binds to Dvl1-3 while the missense point mutation found
in
Lp
perturbs Vangl2 interaction with all three Dvls (
Torban, Wang,
Groulx, & Gros, 2004
). Consistent with the findings in fly where most
PCP proteins show an asymmetric plasma membrane distribution, we
found that a transgenic Dvl2-EGFP fusion protein, capable of rescuing
the stereocilia orientation defects in
Dvl1
/
;
Dvl2
/
mutants, displays
apically restricted asymmetric plasma membrane localization to the
abneural side of the hair cell. The uniform asymmetric localization of
Dvl2-EGFP is disrupted in
Lp/Lp
embryos (
Wang et al., 2005
).
Lp
-dependent asymmetric localization of Fz3 and Fz6 in the sensory hair
cells, utricles, and cristae was reported (
Wang, Guo, et al., 2006
),
suggesting that in mammals a conserved PCP pathway serves as the
underlying mechanism in coordinating stereocilia orientation. Of note,
Fz6
/
mice display misorientation of hairs throughout the body,
implying that the mammalian PCP pathway also controls macroscopic
hair patterning (
Guo, Hawkins, & Nathans, 2004
).
3.2. PCP pathway in neurulation
In addition to the inner ear polarity defects,
Lp
,
Crsh
,
Scy
,
Fz3
/
;
Fz6
/
,
and
Dvl1
/
;
Dvl2
/
mutants all result in a unique neural tube closure de-
fect where the entire neural tube from midbrain to tail fails to close, a severe
congenital neural tube defect termed craniorachischisis in humans (
Curtin
et al., 2003; Hamblet et al., 2002; Kibar et al., 2001; Murdoch et al.,
2001; Murdoch et al. 2003; Wang, Guo, & Nathans, 2006
). Based on
experiments in
Xenopus
in which overexpression of XDsh and Stbm
mutants that blocks convergent extension usually results in similar neural
tube closure defects, the cause of craniorachischisis in these mutants
appears to be due to a failure of convergent extension (
Copp, Greene, &
Murdoch, 2003; Darken et al., 2002; Goto & Keller, 2002; Ueno &
Greene, 2003; Wallingford & Harland, 2002
). In support of this
hypothesis, we found that during neurulation the mouse neural plate
undergoes concomitant lengthening and narrowing, a morphogenetic
process that resembles convergent extension in other vertebrates. Both
Dvl1
/
;
Dvl2
/
and
Lp/Lp
mutants disrupt the coordinated lengthening
