Biomedical Engineering Reference
In-Depth Information
coordinated polarization of cells in a plane of epithelium. While first iden-
tified in
Drosophila
, the same core molecules serve a conserved function in
the regulation of coordinated uniform cellular activities across a plane of cells
in animals as diverse as nematodes to mammals (
Semenov, Habas, Macdon-
ald, & He, 2007
).
3.1. Core PCP molecules
The first demonstration of a role for one of the core PCP molecules in the
orientation of stereociliary bundles was the demonstration of rotated bundles
in the cochleae of
Vangl2
Lp/Lp
mutants (
Montcouquiol et al., 2003
). In this
spontaneous mouse mutant, a missense mutation in the C-terminal cytoplas-
mic domain of
Vangl2
is thought to lead to the destabilization and loss of
function of the protein (
Kibar et al., 2001; Montcouquiol et al., 2006
).
Vangl2
is one of two mammalian homologs of
Drosophila van gogh
(vg)
(
Murdoch, Doudney, Paternotte, Copp, & Stanier, 2001
). Stereociliary
bundles on hair cells in both cochlear and vestibular epithelia appear
phenotypically normal in terms of shape, number, and distribution, but
most bundles are misoriented (
Montcouquiol et al., 2003
). Within the
cochlea, analysis of bundle orientation defects based on position within the
four rows of hair cells indicated an intriguing gradient in which hair cells
located in the single inner hair cell row or in the third row of outer hair cells
were most severely affected with orientations in both rows approaching a
random distribution. In contrast, the average change in orientation for
bundles located in the first row of outer hair cells was significantly less than
in the second or third row of outer hair cells and did not significantly differ
from control in the basal region of the cochlea. This result emphasizes a
common observation for the effects of many PCP mutants within the inner
ear: increased sensitivity in the two most peripheral rows of hair cells, and in
particular, in the third row of outer hair cells. In contrast, measurements of
bundle orientations in the utricle, one of the vestibular epithelia, indicated a
near random distribution (
Montcouquiol et al., 2006
). Finally, overall length
of the cochlear duct was decreased and cellular patterning was disrupted in
Vangl2
Lp/Lp
mutants, indicating a role for Vangl2 and PCP in cochlear
extension. In particular, the apical region of the cochlea, which normally
contains three, or in some cases only two, rows of outer hair cells in a wild-
type animal, contained five to seven rows of outer hair cells in
Vangl
Lp/Lp
mutants (
Montcouquiol et al., 2003
).
Vangl2 and the related Vangl1 are four-transmembrane domain proteins
with a C-terminal PDZ domain. In addition to orientation defects in the
