Biomedical Engineering Reference
In-Depth Information
ligases that are thought to spatiotemporally regulate ubiquitination of diverse
substrates. The PCP phenotype in
Smurf
mutants has been attributed to loss
of asymmetric subcellular localization of Prickle1 due to defective protein
degradation via a Smurf, Par6, and Dvl complex (
Narimatsu et al., 2009
).
Dact1 (Dapper, antagonist of beta-catenin, homolog 1) has been shown
to be important in regulating cytoplasmic PCP components upstream of
PCP signaling. It is thought to modulate PCP signaling via interaction with
the PDZ domain of Dvl (
Wen et al., 2010
).
Dact1
homozygous null mice are
perinatal lethal and exhibit a variety of developmental defects including neu-
ral tube closure defects and shortened tails (
Wen et al., 2010
); however, co-
chleae were not examined in these mice. Dact1 is thought to control
localization and levels of cellular Dvl, disrupting Rho GTPase and JNK.
Dact1 has also been shown to regulate Vangl2 localization during gastrula-
tion via direct protein interaction (
Suriben, Kivimae, Fisher, Moon, &
Cheyette, 2009
). Bicaudal C is another potential candidate for modulation
of Dvl during PCP signaling in the mammalian cochlea as it has been shown
to do so in
Xenopus
and
Drosophila
(
Bouvrette, Sittaramane, Heidel,
Chandrasekhar, & Bryda, 2010; Maisonneuve et al., 2009
).
Finally, it is important to consider that PCP defects have also been
reported in mice carrying mutations in genes that act at time points consid-
erably earlier than the formation of stereociliary bundles. For instance, the
homeodomain protein
Emx2
has been shown to regulate early developmen-
tal events within the inner ear including balancing cell proliferation and dif-
ferentiation. Homozygous
Emx2
knockouts survive until birth but display
shorter cochlear ducts and reduced hair cell numbers with rotated
stereociliary bundles (
Holley et al., 2010
). Classical PCP signaling is not
thought to be directly affected by Emx2, rather the polarity defects observed
in these mice are more likely to be a result of the developmental defects
related to the extension and patterning of the sensory precursor population
that secondarily result in rotated stereociliary bundles. However, consider-
ing that many of the PCP mutations also result in defects in cochlear exten-
sion, separating direct and indirect roles of individual genes in PCP signaling
within the cochlea can be challenging.
5. CILIA AND THEIR ROLE IN PCP
No discussion of PCP in the mammalian inner ear would be complete
without an examination of the role of the kinocilium during cochlear and
inner ear development and bundle orientation. As discussed, kinocilia are
