Biomedical Engineering Reference
In-Depth Information
regulate signal transduction in a number of developmental signaling path-
ways including Sonic Hedgehog signaling (reviewed in
Goetz and Anderson
(2010)
and
Jones and Chen (2008)
. Defects in the biogenesis or maintenance
of cilia cause human pathologies known as “ciliopathies” (
Badano, Mitsuma,
Beales, & Katsanis, 2006
), some of the most frequent manifestations of which
includepolycys ickidneyd sease
Goetz & Anderson, 2010; Jones &
Chen, 2008
)andre inaldegenera ion
Bramall, Wright, Jacobson, &
McInnes, 2010; Ramamurthy & Cayouette, 2009
). Cilium is formed by a
membrane enclosed, microtubule-based axoneme that protrudes into the
extracellular space. It is positioned at the cell apical pole by anchoring to
an underlying basal body and transitional fibers (
Gerdes, Davis, &
Katsanis, 2009
). Vangl2 and other PCP proteins have been implicated in
several aspects of cilia development, polarized localization, and motile
function (
Wallingford & Mitchell, 2011
). PCP proteins Vangl2 (
Guirao
et al., 2010; Ross et al., 2005
), Dvl (
Park, Mitchell, Abitua, Kintner, &
Wallingford, 2008; Park et al., 2006
), and Fat4 (
Saburi et al., 2008
) have
been detected by double immunofluorescence with cilia-specific markers at
the base of cilia in certain ciliated cell types, while in other ciliated cell
types, Vangl2 appears to be solely localized to the lateral membrane and
not at the base of the cilium (
Borovina, Superina, Voskas, & Ciruna,
2010; Song et al., 2010
), likely reflecting a different tissue-specific
requirements for Vangl2 in the cilia-related processes. Gene silencing
experiments and studies with dominant-negative mutant alleles in model
organisms such as zebrafish and
Xenopus
have shown that ablation of
trilobite
(
Vangl
)(
Antic et al., 2010; May-Simera et al., 2010; Mitchell
et al., 2009
),
Dvl
(
Mitchell et al., 2009; Park et al., 2008
),
fuzzy
(
Gray
et al., 2009; Park et al., 2006
), and
inturned
(
Park et al., 2006; Zeng,
Hoover, & Liu, 2010
) causes a general reduction in cilia number and cilia
length in different ciliated cell types. Such reduction was linked to the
defects in the apical docking of basal bodies and/or defects in the
organization of the cortical actin network which supports anchoring of
the basal bodies beneath apical surface. Mammalian Vangl2 has been
shown to be essential for asymmetric positioning and tilting of primary
cilia. Altered positioning of basal body and cilia in posterior notochord
cells causes altered nodal flow in embryos devoid of Vangl protein
function (homozygous
Vangl1
/
Vangl2
double mutants) (
Song et al.,
2010
), although ciliogenesis
per se
is not affected in these cells. Likewise,
ablation of
Vangl2
(
Guirao et al., 2010
) results in altered ciliary alignment
in the maturing ependymal cells lining cerebral ventricles that ultimately
