Biomedical Engineering Reference
In-Depth Information
Wnt/PCP pathway still largely rely on genetic screening in
Drosophila
or
findings from forward or reverse mouse genetics, as the most reliable func-
tional readout of PCP is still based on
in vivo
phenotypic analysis. The Rho
family GTPases (Rho, Rac, Cdc42) and JNK pathway have been demon-
strated to be the downstream transducers of core PCP proteins to regulate
cell morphology (
Kikuchi, Yamamoto, & Kishida, 2007; Schlessinger,
Hall, & Tolwinski, 2009; Tada & Kai, 2009
). Because of these, people
have attempted to use AP1- or ATF2-luciferase reporter (downstream
transcription factors of JNK pathway) or c-Jun/JNK phosphorylation as
readouts for Wnt/PCP pathway (
Ohkawara & Niehrs, 2011; Park &
Moon, 2002; Shafer, Onishi, Lo, Colakoglu, & Zou, 2011
). However, it is
still largely unclear whether JNK is a major mediator of PCP in vertebrates
in vivo
as JNK activity can be regulated by many other signaling pathways
(
Weston & Davis, 2002, 2007
). Furthermore, it is still questionable
whether these cell morphology regulators should be placed into the core
PCP pathway. Importantly, those proteins which disruption changed cell
morphology should not be simply interpreted as PCP proteins/effectors.
They could be two distinct pathways both regulating cell morphology
(
Lapebie, Borchiellini, & Houliston, 2011
). Lack of a simple and reliable
molecular readout of Wnt/PCP pathway has severely hindered our
understanding of signal transduction in the Wnt/PCP pathway.
Establishment of PCP is likely to be regulated at the protein level by asym-
metrical protein localization, not at the transcriptional level as none of the core
PCP proteins is a transcription factor. Recently, a novel signaling mechanism
underlyingWnt5a-dependent PCP establishment in mouse embryonic devel-
opment has been identified (
Gao et al., 2011
). Vangl2, a core PCP protein, is
phosphorylated at two highly conserved clusters of serines/threonines in re-
sponse to Wnt5a in a Wnt5a-dose-dependent manner. As Vangl2 phosphor-
ylation is required for Wnt/PCP signal transduction, it is likely that a Wnt5a
signaling gradient can theoretically orient the cells it signals to by regulating
the Vangl2 protein activity in each cell. These findings have opened new
doors to further understanding Wnt/PCP signal transduction.
2.4. Wnt signaling gradients establish PCP
Although Wnt proteins, especially Wnt5 and Wnt11, have been strongly
implicated in regulating PCP in vertebrate, a big question remained: do they
indeed provide directional cues to initiate PCP or are they only required for
PCP establishment as permissive signals?
