Biomedical Engineering Reference
In-Depth Information
left/right asymmetry, Inv mutants formed cystic kidneys. Sequencing of the
Nphp2 gene revealed that it shared high homology with fly Dgo. Indeed,
Invs and Dgo can substitute for each other functionally (
Simons et al., 2005
).
Inversin physically and functionally interacts withDvl (
Simons et al., 2005
).
Inversin
has been proposed as a Wnt pathway switch, supporting noncanonical
signaling while repressing canonical signaling. Whether this function is active
during kidney development and contributes to the defects seen in mutant
kidneys is still under debate. Analysis of the expression of a Lef/Tcf/
b
-catenin
reporter in
Inv
mutants did not show any changes (
Sugiyama, Tsukiyama,
Yamaguchi, & Yokoyama, 2011
). However, whether these reporters truly
report all Wnt activity is still not clear. A more detailed analysis of cellular
phenotypes or genetic studies would certainly shed light onto this question.
4.2.2 Tubule elongation
4.2.2.1 Vangl2
A possible direct role for PCP signaling in renal tubule morphogenesis
comes from examination of the
Lp
mice. Renal medulla formation is defec-
tive in both heterozygous and homozygous mutants (
Yates et al., 2010
;
Q. Ren and J. Yu unpublished observations).
In the developing renal medulla,
Vangl2
is expressed at modest levels in
both the ureteric bud epithelium and the interstitium and weakly in the
loops-of-Henle ( J. Yu, unpublished observations). The nature of the
Lp
mutation means that Vangl2 activity is compromised in all these cell types
in
Lp
mutants. Thus, it is still unknown whether Wnt/PCP signaling is
required cell autonomously within the renal tubules or within the inter-
stitium. This question of where the PCP pathway is active and functioning
needs to be addressed with cell type-specific ablation of
Vangl2
or other
Wnt/PCP signaling components. Interestingly, contrary to what is
observed in flies, Vangl2 protein does not show obvious planar-polarized
localization in any cell types in the kidney (T. J. Carroll & J. Yu,
unpublished observations).
Interestingly, the presence of a single
Lp
allele on the
Fat4
homozygous
mutant background leads to an enhancement of tubular dilation (
Saburi
et al., 2012
). Interpretation of this result is difficult. The simplest explanation
is that both genes are regulating PCP but they function in separate, parallel
pathways. Although reduction of Vangl2 activity alone does not lead to sig-
nificant tubular dilation or cyst formation, its function is accentuated in the
context of
Fat4
loss. Once again, it will be interesting to assess PCP includ-
ing cellular orientation in both individual and compound mutants as well as
assessing the specific cell types in which these two gene products function.
