Biomedical Engineering Reference
In-Depth Information
McMahon, 2005
). However, mice that have had
Wnt9b
deleted in the
nonbranching/stalk portion of the collecting ducts or mice carrying a
hypomorphic allele of
Wnt9b
develop cysts (
Karner et al., 2009
).
Interestingly, even though
Wnt9b
is expressed in the collecting ducts,
cysts form in all nephron segments. In fact, cysts are first apparent in the
proximal tubules.
From the earliest stages of development examined (E13.5 onward),
Wnt9b
mutants show a significant increase in the number of cells making
up the cross-sectional circumference of the collecting ducts and proximal
tubules compared to wild-type littermates (
Karner et al., 2009
). As men-
tioned, at these early stages, cell division is random and
Wnt9b
mutants have
no significant change in the orientation of their mitotic spindles, suggesting
that the cause of the tubular dilation in these mutants is defective cell move-
ment/CE. Indeed, although the epithelial cells of mutants are elongated sim-
ilar to what is seen in wild-type tubules, their orientation relative to the
proximal-distal axis becomes randomized (
Karner et al., 2009
)(
Fig. 8.4
).
This sort of defect in cell orientation would be predicted to lead to defects
in mediolateral intercalation (if such a process is occurring), which could
contribute to tubule dilation.
Around the time of birth, cell division becomes tightly oriented
throughout the collecting duct system (excluding the still branching UB
tips). Interestingly, when noncystic collecting ducts were examined in post-
natal
Wnt9b
mutants, it was found that the orientation of cell division was
randomized (
Karner et al., 2009
). If the orientation of cell division is con-
trolled in part by cellular orientation, this makes sense and the same cellular
defect could be affecting both CE movements and oriented cell division in
Wnt9b
mutants. However, it is possible that
Wnt9b
regulates multiple aspects
of PCP that regulate distinct cellular processes.
Although it has been shown that
Wnt9b
signals through
b
-catenin to the
mesenchyme during the initial stages of mesenchymal-to-epithelial transition
(
Carroll et al., 2005; Karner et al., 2011
), the target cell and signal transduction
cascade used during tubule morphogenesis are still not clear.
Wnt9b
could be
directly affecting PCP within the epithelia or it could be acting through the
interstitium as Wnt7b does. Although
Karner et al. (2009)
found no defects in
the expression of
b
-catenin targets in
Wnt9b
mutants, most of these are
expressed in the epithelia. As the target cell of
Wnt9b
is unknown, the
utility of epithelial targets is unknown. The authors did find decreased
levels of GTP-bound (active) Rho and phosphorylated Jnk (targets of
noncanonical Wnt signaling) in mutants, although these effects could also
be indirect. Clearly, more work needs to be done in this field.