Biomedical Engineering Reference
In-Depth Information
orientation of different structures including the eye unit (ommatidium) and
in the uniform polarity of certain appendages such as the hair (trichome) on
wing cells. Genetic screens have identified several so-called core PCP genes
in which mutations cause defects in polarity of these structures:
frizzled
(
fz
),
disheveled
(
Dsh
),
prickle
(
pk
),
Van Gogh
(
Vang
),
flamingo
(
fmi
), and
diego
(
dgo
)
(
Gubb & Garcia-Bellido, 1982
); extensively reviewed by (
McNeill, 2010;
Simons & Mlodzik, 2008
;
Goodrich & Strutt, 2011
). Genetic interaction
screens
in vivo
, protein:protein interaction experiments
in vitro
,subcellular
colocalization studies, and analysis of mosaic clones on fly wings
demonstrate that the core PCP proteins assemble into dynamic membrane-
bound complexes that rearrange during establishment of PCP in flies. Fz is
a 7-transmembrane domains protein that recruits cytoplasmic Dsh to the
membrane. Dsh is a modular protein consisting of DIX, PDZ, and DEP
domains that can bind Pk, Vang, and Dgo. In flies, Vang can bind Dsh,
Pk, and the cytoplasmic ankyrin-repeat protein Dgo. The mechanism by
which these proteins establish PCP in flies involves their asymmetric
distribution and selective enrichment that culminate in the appearance of
two polarized membrane-bound complexes: Dsh/Fz at the distal side and
Vang/Pk at the proximal side of wing epithelial cells. This asymmetry in
distribution of the core PCP proteins establishes critical positional
information. Fmi, a 7-TM protein with a long extracellular domain
encoding nine cadherin domains (that enable homotypic interactions),
interacts with both Dsh/Fz and Vang/Pk complexes stabilizing and
propagating the PCP signal through a “domino” effect (
McNeill, 2010;
Simons & Mlodzik, 2008; Goodrich & Strutt, 2011
). Genetic screens in
flies have also identified cadherin proteins Fat (Ft), Dachsous (Ds), and the
Golgi kinase Four-jointed (Fj) as additional general PCP genes (
Rawls,
Guinto, & Wolff, 2002; Yang, Axelrod, & Simon, 2002; Zeidler,
Perrimon, & Strutt, 1999
) that act to stabilize and propagate the PCP
signal. Other evidence suggest that the fat/dachsous pathway may act in
parallel to the frizzled/Flamingo pathway (
Casal, Lawrence, & Struhl, 2006
).
Finally, the proteins Fuzzy and Inturned have also been identified as wing-
specific PCP “effector” genes in flies (
Collier & Gubb, 1997; Gubb &
Garcia-Bellido, 1982
).
This PCP pathway is conserved in mammals and has been the focus of
intense investigation in the past few years. These studies have shown that
PCP genes play a critical role in the development and maintenance of broad
range of tissues and organs. In mammals, there exist 2
Vangl
genes, 10
Frizzled
(
Fz
), 4
Prickle
(
Pk
), 3
Dishvelled
(
Dvl
), 3
Flamingo
(
Celsr
), 1
Diego
