Biomedical Engineering Reference
In-Depth Information
physical basis for this asymmetry is not yet known, asymmetric
conformations, posttranslational modifications, or unequal stoichiometries
are possible explanations. While this asymmetric Fmi homodimer model
remains our favored blueprint for further exploration of PCP signaling
across the adherens junction, several groups have suggested alternative
mechanisms. While it is universally agreed that the mutual recruitment
between Fz and Vang complexes depends on the involvement of Fmi
homodimers, there is disagreement regarding whether Fmi dimers
asymmetrically transmit information between cells or act solely as a
structural bridge to stabilize the Fz-Vang interaction, through which such
information might flow. Wu et al. have presented evidence for a direct
interaction between the extracellular CRD domain of Fz and Vang
in vitro
(
Lawrence, Casal, & Struhl, 2004; Wu & Mlodzik, 2008
).
Physiological relevance of this interaction was argued based on the loss of
PCP signaling observed when the CRD of Fz was replaced with that of
the PCP-irrelevant
Drosophila
Fz2 gene. This negative result is discrepant
with Chen et al.'s observation that an Fz derivative lacking the CRD can
provide some PCP signaling activity. These dramatic differences in
rescuing efficiency might reflect differences in protein expression or
folding efficiency and remain an important puzzle to be resolved.
Another clear distinction between the two models just described
involves the directionality of polarity information transmission. According
to the asymmetric Fmi homodimer model, polarity information flows in
both directions such that cells on either side respond to the other
(
Fig. 2.2C
). The direct Fz-Vang interaction model as articulated by several
groups argues for a unidirectional information flow in which Vang does not
send information across the adherens junction but instead acts only as signal-
ing receptor for the CRD domain of Fz (
Fig. 2.2D
)(
Lawrence et al., 2004;
Wu & Mlodzik, 2008
). This unidirectional model, however, does not
readily explain how (at borders of
fz
-
vang
twin clones) cells expressing
Vang but not Fz cause repolarization of adjacent cells expressing Fz but
not Vang (
Strutt & Strutt, 2007
).
A third, independent, investigation, by Strutt et al., contributed obser-
vations to this discussion that, while not providing resolution, must be
accommodated by a correct model (
Strutt & Strutt, 2008
). Consistent with
the asymmetric Fmi homodimer model, Strutt et al. presented evidence
suggesting that Fmi exists in two alternative forms, preferentially interacting
either with Fz or with Vang, with the bias involving differential binding to
the C-terminal cytoplasmic tail of Fmi. Furthermore, they found that Fmi
