Biomedical Engineering Reference
In-Depth Information
homolog of
Drosophila scribble
(
scrib
), encodes a leucine-rich protein with
four PDZ domains. In
Drosophila scrib
mediates both apical-basal and planar
polarity (
Bilder, 2004
;
Courbard et al., 2009
;
Macara, 2004; Nelson, 2003
).
However,
Scrib
was first identified as a PCP gene in the
circletail
mouse
mutant. This spontaneous point mutation results in a severely truncated
Scrib protein, craniorachischisis, and misoriented cochlea hair cells
(
Montcouquiol et al., 2003; Murdoch et al., 2003; Rachel et al., 2002
).
Further,
Scrib
interacts genetically with
Vangl2
and Scrib protein has been
shown to bind to Vangl2 via its PDZ domain. Scrib is thought to
function in the asymmetric targeting of Vangl2-containing PCP
complexes (
Montcouquiol et al., 2006
). Asymmetric localization of
Vangl2 is lost in Scrib
crc
mutants, confirming a role for Scrib in Vangl2
localization.
An additional cytoplasmic protein that can also modulate inner ear PCP
is
protein tyrosine kinase 7
(
Ptk7
)(
Lu et al., 2004
), which encodes a tyrosine
kinase signal peptide, seven immunoglobulin domains, a single transmem-
brane domain, and an intracellular tyrosine kinase domain. Ptk7 has been
shown to interact directly with Wnt ligands as well as with
b
-catenin
(
Peradziryi et al., 2011; Puppo et al., 2011
); however, its role in PCP
signaling is likely via its interactions with Rack1 and Pkc
d
1, known
effectors of Dvl membrane translocation (
Wehner, Shnitsar, Urlaub, &
Borchers, 2011
). Rack1 is needed for Ptk7-mediated membrane
localization of Dvl, one of the earlier events during PCP signaling. The
Xenopus
homolog of Ptk7 has been implicated in convergence and
extension and fz-dependent localization of disheveled (
Lu et al., 2004;
Shnitsar & Borchers, 2008
). In mouse, Ptk7 has been shown to be
essential for polarized cell motility and convergence and extension (
Yen
et al., 2009
). Various mouse mutants of
Ptk7
display craniorachischisis
and disrupted hair cell orientation and interact genetically with
Vangl2
and
Celsr1
mutants (
Lu et al., 2004; Paudyal et al., 2010
). In addition,
Ptk7
has recently been shown to regulate the activity of Myosin II which
plays a role in both cochlear convergence and extension and bundle
orientation (
Lee et al., 2012
).
3.6. Downstream targets
Downstream effects of PCP signaling result in the regulation of the actin
cytoskeleton via the family of Rho GTPases. Rho family members include
Rho, Rac, and Cdc42 molecules, central regulators of actin dynamics,
