Biomedical Engineering Reference
In-Depth Information
kidney, cell division is also polarized and the polarized cell division was
disrupted in the Wnt7b mutant resulting in an elongation defect of the
renal collecting duct. It is not clear whether Wnt7b itself is involved in the
regulation of oriented cell division through PCP. Wnt7b-dependent
expression of
Wnt4
and/or
Wnt11
in the renal
interstitium may also
regulate PCP pathway (
Yu, 2011; Yu et al., 2009
).
These evidence indicate that Wnt morphogens regulate PCP in verte-
brate, although Wnts have not been found to control PCP in
Drosophila
so far. However, it is not entirely clear whether Wnt morphogens act as
global cues in any of the system.
2.3. Wnt signaling
Wnts are a large family of secreted molecules that can transduce their signals
through several different pathways (
Fig. 11.2
)(
Angers & Moon, 2009;
Logan & Nusse, 2004
). The best-understood pathway is the canonical
pathway that is transduced by stabilizing
b
-catenin. This pathway is
evolutionarily conserved and controls many processes of development
and adult tissue homeostasis (
Clevers, 2006; MacDonald, Tamai, & He,
2009
). In this pathway, Wnt proteins bind to their coreceptors Frizzleds
and Lrp5/6 on the cell surface leading to phosphorylation of Lrp5/6,
which then inactivates the
b
-catenin destruction complex containing
Axin/GSK3/APC by recruiting Axin to the cell membrane (
MacDonald
et al., 2009
). The stabilized
b
-catenin accumulates in the cytoplasma and
then enters the nucleus to form a complex with TCF/Lef and activate
target genes expression. In the absence of Wnt ligands,
b
-catenin is
phosphorylated by GSK3 in the destruction complex and degraded
(
Macdonald, Semenov, & He, 2007; MacDonald et al., 2009
). According
to the ability of Wnts to induce
b
-catenin accumulation in the nucleus,
Wnt family members were divided into two distinct classes. For example,
Wnt1, Wnt3a, and Wnt8 (canonical Wnts) strongly stabilize
b
-catenin
but other Wnts like Wnt5a and Wnt11 (noncanonical Wnts) could not.
Instead, Wnt5a represses canonical Wnt signaling (
Mikels & Nusse, 2006;
Topol et al., 2003; Torres et al., 1996; Westfall et al., 2003
). However,
other evidence showed that context-dependent combination of Wnt
receptors, rather than Wnt proteins themselves, may play more important
roles in determining which branch, “canonical” or “noncanonical,” Wnt
ligands signal through (
van Amerongen, Mikels, & Nusse, 2008
). It is
likely that all Wnts can signal through both the “canonical” and the