Biomedical Engineering Reference
In-Depth Information
which asymmetric protein localization arises. Our current understanding is
based largely on experimental studies with
Drosophila
wing epithelium, in
combination with mathematical simulations that examine the properties
of proposed models. While studies with vertebrate models have to date
yielded less mechanistic insight, numerous observations suggest substantial
mechanistic conservation (
Mitchell et al., 2009; Sienknecht, Anderson,
Parodi, Fantetti, & Fekete, 2011
).
We begin with a brief discussion of the three modules of planar
polarity genes and propose a hierarchical structure, a model first developed
almost a decade ago (
Tree, Ma, & Axelrod, 2002
). Despite the elapsed time,
the mechanisms underlying this organization have not been revealed. We
believe that the model has proved to be a valid general framework for
understanding PCP, despite some recent challenges, and that clarifying
mechanisms will soon emerge. Given its controversial nature, the model
deserves a quick revisit here.
2. REVISITING THE THREE-TIERED HIERARCHY OF PCP
2.1. Original three-tiered hierarchy model
The existence of planar-polarized features of many types of epithelial struc-
tures has enabled extensive genetic studies of the genes and molecular
pathways that control PCP. On the basis of phenotype, as well as genetic
interaction, cell biological, and biochemical studies, these components
can be classified as belonging to one of three distinct functional modules.
We have argued previously that these three modules interact hierarchically
(
Tree, Ma, et al., 2002
).
A highly conserved core module including the proteins Frizzled (Fz),
Disheveled (Dsh), Van Gogh (Vang, aka Strabismus), Prickle (Pk), Flamingo
(Fmi), and Diego (Dgo) produces molecular asymmetry within and between
cells. Distinct proximal (Vang, Pk, and Fmi) and distal (Fz, Dsh, Dgo, and
Fmi) complexes segregate to opposite sides of the cell, where they interact
with the opposite complex in the neighboring cell at or near the adherens
junctions. Feedback mechanisms between components of this key module
ensure exclusive asymmetric protein localization during planar polarization
by exclusion of oppositely oriented complexes from adjacent regions of the
cell cortex and by recruitment of the opposite complex in the neighboring
cell (
Goodrich & Strutt, 2011
) The result is an amplification of localization
asymmetry of these core PCP proteins, producing steep intracellular gradi-
ents from any initial biasing input. This polarity amplification is necessarily
