Biomedical Engineering Reference
In-Depth Information
Neither were significant changes noted in the expression of other core
determinants, nor were the rates of proliferation or apoptosis affected. There
was also no description of defects in any aspect of PCP in these mutants.
During ureteric bud branching morphogenesis, dilated ampullae are re-
solved into two stalks with narrower diameter. This process may involve
PCP-dependent cell rearrangements. Cell movements have been observed
in ureteric bud tips during branching morphogenesis. It will be interesting to
examine whether directional cell movements occur during branching mor-
phogenesis and, if so, whether Wnt/PCP signaling affects this process cell
autonomously in the ureteric bud epithelium. However, for now, the
mechanism underlying this phenotype is unclear.
4.2.1.2 Fz4/8
Fz4
and
Fz8
are expressed specifically in the ureteric bud epithelium during
early kidney development and mice lacking both genes showmildly disrupted
branching morphogenesis (
Ye, Wang, Rattner, & Nathans, 2011
). Fz recep-
tors can act within the core PCP pathway, the canonical Wnt pathway, or the
noncanonical Wnt pathway. In
Fz4/8
mutants, it is not clear which aspect of
Fz signaling is disrupted. The mutants show some similarities to
Wnt11
mutants including reduced branching and decreased levels of the
Ret
receptor
tyrosine kinase in the UB and its ligand
Gdnf
inthemesenchyme(
Majumdar,
Vainio, Kispert, McMahon, & McMahon, 2003
). Indeed,
Wnt11
is able to
signal through
Fz4
and
Fz8 in vitro
(
Ye et al., 2011
). However,
Wnt11
can
activate both canonical (
Tao et al., 2005
) and noncanonical (
Garriock,
D'Agostino, Pilcher, & Krieg, 2005; Marlow, Topczewski, Sepich, & Solnica-
Krezel, 2002; Matsui et al., 2005; Tada & Smith, 2000; Takeuchi et al., 2003
;
Ye et al., 2011
) pathways providing little insight into pathway usage in the kidney.
It is important to note that the
Fz4/8
mutant UBs also show some sim-
ilarity to kidneys that have had
b
-catenin removed from the UB (reduction
of Ret/Gdnf expression and activity, reduced branching, and reduced pro-
liferation rates) (
Marose, Merkel, McMahon, & Carroll, 2008
). Although
the authors did not examine the expression of
b
-catenin targets such as
Axin2
in
Fz4/8
mutants, these data may support a canonical role for
Fz4/8
in UB branching. However, at this point, it is impossible to rule
out noncanonical or PCP roles for the Frizzleds.
4.2.1.3 Inversin
Inversin, encoded by the
Nphp2
gene, was identified by positional cloning of
the Inv mouse that was generated in a mouse mutagenesis screen (
Morgan
et al., 1998; Otto et al., 2003; Simons et al., 2005
). Along with defects in
