Biomedical Engineering Reference
In-Depth Information
the core PCP proteins remain unclear. For a large part, functional redundancy
between various members of the fat and dachsous families may mask the role
of individual proteins. For example,
Fat1
mutant mice show no PCP pheno-
type (
Ciani, Patel, Allen, & ffrench-Constant, 2003
). It may be necessary to
generate multiple gene knockout animals in order to tease apart the molecular
mechanisms, which may also be tissue and time dependent.
4. UPSTREAM REGULATORS OF PCP
As discussed, appropriate localization of PCP proteins represents a key
step in the generation of polarity and mislocalization of PCP proteins
can result in phenotypic defects that are indistinguishable from phenotypes
observed as a result of the complete deletion of a PCP gene. These obser-
vations have led to an emerging understanding of the importance of highly
specific synthesis, trafficking, and targeting of proteins to particular regions
of the cell. One such process is the transport of proteins from the endoplas-
mic reticulum (ER) to the Golgi apparatus. Surprisingly, “classic” PCP de-
fects including craniorachischisis and misorientation of cochlear hair cells
have been observed in
Sec24b
mutants (
Merte et al., 2010; Wansleeben
et al., 2010
).
Sec24b
encodes a cargo-sorting coat protein that forms the
Cop II-coated vesicles required for ER to Golgi transport (
Wendeler,
Paccaud, & Hauri, 2007
). Both
Vangl2
and
Scrib
have been shown to
genetically interact with
Sec24b
, and evidence suggests that Sec24b
selectively transports Vangl2 from the ER to the Golgi (
Merte et al.,
2010; Wansleeben et al., 2010
). Of note is that the genes encoding Sec23
and Sec24 proteins in
Drosophila
have been shown to be required for
apical-basal cell polarity (
Norum et al., 2010
). As such, these data
implicate a high degree of selective protein sorting and trafficking
upstream of protein localization.
The concept of regulated protein transport of PCP proteins to the cell
membrane has been studied in the
Drosophila
wing epithelium. Polarized
localization of fz was shown to be regulated via vesicular transport along
proximodistally oriented microtubules and disruption of microtubules
perturbed fz localization (
Shimada, Yonemura, Ohkura, Strutt, & Uemura,
2006
). Based on these results, a similar mechanism for the targeting of other
PCP proteins in invertebrates as well as in vertebrates seems likely. Protein
degradation is another mechanism by which subcellular protein levels can be
regulated. Intriguingly, PCP phenotypes have been observed in
Smurf1
and
Smurf2
mutant mice (
Narimatsu et al., 2009
).
Smurf
genes encode ubiquitin
