Biomedical Engineering Reference
In-Depth Information
them are characterized by the presence of cystic kidneys (
Hildebrandt,
Benzing, & Katsanis, 2011
).
Genetic studies have identified a striking reciprocal relationship between
PCP genes and genes underlying ciliopathies suggesting that both pathways
likely intersect at cilia function: (a) Cystic disease occurs upon loss of cilia
function and/or loss of oriented cell division, both of which are regulated
by PCP signaling in certain tissues (
Fischer et al., 2006
); (b) Several PCP
proteins including Vangl2 are present at the base of cilia in certain cells
(
Guirao et al., 2010; Park et al., 2006, 2008; Ross et al., 2005
); (c) Mice
bearing independent mutations in
Fat4
(
Saburi et al., 2008
)or
Inversin
(relative of
Diego
that is mutated in the Nephronophthisis type 2 in
humans (
Simons et al., 2005
)) display cystic kidneys. Importantly, the
effect of
Fat4
knockdown on renal cystic phenotype is exacerbated by
crossing
Fat4
mutant to
Vangl2
Lp/
þ
(
Saburi et al., 2008
). Inversin was also
shown to form a protein complex with Vangl2 and Dvl2 (
Simons et al.,
2005
); (d)
Bbs1
/
,
Bbs4
/
,
Bbs6
/
, and
Mkks
/
mutants display PCP
defects in the cochlea (orientation of hair cells), while
Bbs4
/
mutants
additionally exhibit exencephaly and open eyelids. Notably, all
Bbs
and
Mkks
phenotypes in mice are exacerbated by introducing a single copy
of mutated
Vangl2
in
Vangl2
Lp/
þ
heterozygotes (
Ross et al., 2005
).
In addition, Bbs8 has been shown to physically interact with Vangl2
(
May-Simera et al., 2010
).
The data obtained in mice with mutations of structural ciliary proteins
Ift88 and Kif3a are less clear. Excision of
Kif3a
in renal tubules causes cystic
kidney disease, with mutant tubular cells displaying defective orientation of
mitotic spindles—a well-established PCP defect (
Davenport et al., 2007;
Pazour et al., 2000
). This suggests that cilia integrity is crucial for normal
PCP signaling. However, subcellualr localization of Vangl2 protein is not
affected in cochlea of
Ift88
/
and
Kif3a
/
mouse mutants (
Jones et al.,
2008
), suggesting that the PCP pathway may also act upstream from cilial
proteins.
In kidney, Vangl2 is developmentally expressed at E9.5 in mesonephric
ducts and tubules. At E16.5, Vangl2 protein is prominently expressed in cells
and tubules derived from the ureteric bud (ureteric bud tips, collecting
duct), as well as in S-shaped bodies derived from the metanephric mesen-
chyme, where it is present at cell:cell contacts and at basolateral surface
(
Babayeva, Zilber, & Torban, 2011; Torban et al., 2007
). Vangl2 is also
expressed in glomeruli at the basolateral side of podocytes (
Babayeva
et al., 2011
). Studies in
Lp/Lp
mice identify kidney abnormalities: smaller
