Biomedical Engineering Reference
In-Depth Information
the interstitium or nephron progenitors and the branching defects seen in
mutants are indirect effects caused by disrupted communication between
oneof these cell types and theUB.However, definitive conclusionswill require
analysis of kidneys with tissue-specific ablation of these genes.
4.1.2 Tubule diameter establishment/maintenance
Dchs1
and
Fat4
mutants show dilated distal nephron segments during em-
bryogenesis (
Mao et al., 2011
).
Fat4
mutants show defects in the orientation
of cell division in postnatal collecting ducts (
Saburi et al., 2008
). Whether
this is the cause of tubular dilation is not clear although orientation of cell
division has been implicated in maintaining tubule diameter in other mouse
models (
Fischer et al., 2006
).
Although
Fat4
and
Dchs1
mutants both show kidney defects, no defects
are observed in kidneys lacking the only known Fj ortholog,
Fjx1
(
Saburi,
Hester, Goodrich, &McNeill, 2012
). Although this finding in itself is not all
that surprising (mutation of
Fj
alone has a relatively mild phenotype in the fly
wing),
Fjx1
does not seem to genetically interact with
Fat4
in the developing
kidney (
Saburi et al., 2012
). There are a number of possible explanations for
this finding. It is possible that there is another functional homolog of
Fj
in the
mouse. A second possibility is that
Fat4
and
Dchs1
are not regulating PCP
during kidney tubule morphogenesis. (
Fat4
and
Fjx1
do show strong genetic
interaction in other tissues.) The final possibility is that the interaction be-
tween
Fjx1
and
Fat4
(and
Dchs1
?) is not conserved in mouse kidneys. Con-
sistent with this last possibility, unlike Drosophila, in the mouse kidney,
Fjx1
does not appear to be expressed in the same cells as
Fat4
or
Dchs1
(
Carroll &
Das, 2011; Mao et al., 2011
). Further analysis will need to be performed to
determine which, if any, of these scenarios is correct.
4.2. The core pathway
4.2.1 Branching morphogenesis
4.2.1.1 Vangl2
Although many of the core determinants are expressed in the developing
kidney, there is relatively little known of their function.
Yates et al.
(2010)
recently described the phenotype of the
Loop-tail
(
Lp
) mice that bear
a point mutation in the
Vangl2
gene (ortholog of the Drosophila core PCP
determinant
Vang/Stbm
) that produces a potential dominant-negative mu-
tation. Reduced ureteric bud branching morphogenesis was observed in
mutant kidneys from E13.5. The mutant kidneys are most significantly re-
duced in size along their anterior-posterior axis.
