Asymmetric Protein Localization in Planar Cell Polarity: Mechanisms, Puzzles, and Challenges - Current Topics in Developmental Biology - page 38

epistasis suggestive of this architecture ( Lee & Adler, 2002; Yang et al.,
2002 ). Upon its description, the global module was placed upstream of
the core module by epistasis experiments in the eye ( Yang et al., 2002 )
and by the simple yet powerful observation that core PCP proteins are
incorrectly aligned within global mutant wing clones ( Ma et al., 2003 ).
This three-tiered hierarchy model suggests a linear relationship between
the global-, core-, and tissue-specific modules, in which the global module
translates relatively shallow transcriptional gradients into subtle subcellular
gradients, the core simultaneously amplifies subcellular asymmetry and
locally aligns polarity, and the tissue-specific modules read out polarity cues
to produce morphological or cell fate asymmetry. Though the linear
relationship of the modules can be inferred from the above observations,
the nature of the molecular interactions between the three tiers remains
largely unknown, and the lack of detailed mechanistic knowledge of the
information flow between modules leaves open the possibility of other
architectures for the relationship between modules.
The most direct challenges to a strictly linear three-tiered hierarchy
model come from genetic studies of denticle polarity in the Drosophila adult
abdomen and larval epidermis ( Casal, Lawrence, & Struhl, 2006; Donoughe
& DiNardo, 2011; Repiso, Saavedra, Casal, & Lawrence, 2010 ). Two main
observations have been proposed to be incompatible with the linear model.
First, in both larval denticles and adult abdomen, double mutants
constructed between components of the upstream global module and the
core amplification module display stronger polarity defects than single
mutants of each module alone ( Casal et al., 2006; Donoughe & DiNardo,
2011; Repiso et al., 2010 ). Such enhancement of mutant phenotype has
been argued to suggest that the upstream module and the core module
can affect the downstream effectors (controlling denticle polarity) in
parallel. Second, overexpression of upstream module components has
been shown to alter denticle polarity in the abdomen even in the absence
of an intact core signal amplification module ( Casal et al., 2006 ). This
was similarly interpreted to suggest the existence of a direct link from
global directional cue to the tissue-specific polarity readout. While it is
plausible that the linear three-tiered model is indeed an incorrect
universal description of planar polarity signaling, as these interpretations
suggest, we argue that there is also an important interpretive flaw that
renders the conclusions of both experiments ambiguous. A parallel
relationship between the modules was inferred from the absence of an
epistasis

relationship between the global and the core components;