Biomedical Engineering Reference
In-Depth Information
inner ear, homozygosity for the
Vangl2
Lp
mutation also results in
craniorachischisis, a defect that arises from defects in neural tube closure,
a process that is also regulated by the PCP pathway (
Mullick, Trasler, &
Gros, 1995; Ueno & Greene, 2003; Ybot-Gonzalez et al., 2007
).
Mutations in
Vangl1
have been associated with human neural tube defects
(
Kibar et al., 2007
), but a homozygous
Vangl1
gene trap (
Rachel et al.,
2012
;
Rachel, Wellington, Warburton, Mason, & Beermann, 2002
) line,
encoding a severely truncated nonfunctional version of the protein,
displayed no neural tube defects and only mild stereociliary bundle
orientation defects (
Torban et al., 2008
). Double heterozygous animals
for
Vangl1
gt
and
Vangl2
Lp
did develop craniorachischisis and had severely
rotated cochlea hair cells, suggesting a degree of functional redundancy
between Vangl1 and Vangl2 in the cochlea and neural tube.
In an effort to identify the basis for the orientation defects in
Vangl2
Lp/Lp
mice, the migration of developing kinocilia was compared in control and
mutant cochleae (
Montcouquiol et al., 2003
). As described above, develop-
ing kinocilia typically undergo a directionally biased migration from the
center of the lumenal surface of each developing hair cell toward the lateral
edge. While this migration still occurred in hair cells from
Vangl2
Lp/Lp
mutants, the directional bias was disrupted. Moreover, a direct correlation
between deviation in the directional bias and final bundle orientation was
observed, suggesting that
this defect underlies the orientation defects
observed in these animals.
Subsequent studies have demonstrated similar phenotypes, although
with some intriguing caveats, in cochleae from mice with mutations in
other core PCP genes. These include targeted double mutants for
Frizzled
3
and
Frizzled 6
(
Wang, Guo, & Nathans, 2006
), which seem to be func-
tionally redundant in cochlear PCP, missense mutants for
Celsr1
(one of
three mammalian homologs of flamingo) (
Curtin et al., 2003
), and
targeted mutations in
Disheveled
(
Dvl
)
1
,
2
,or
3
(
Etheridge et al., 2008;
Wang, Hamblet, et al., 2006
). Intriguingly, the degree of bundle
misorientation and the specific hair cell populations that are effected in
each of these mutant models are somewhat variable. While the third
row of outer hair cells is universally effected, inner hair cells are
misoriented in some models (
Fz3/6
) but not in others (
Dvl
). These
results presumably indicate differing degrees of functional compensation
but may also provide clues regarding the nature of the cell-cell
communication that acts to propagate the polarizing signal
from one
row of hair cells to the next.
