Biomedical Engineering Reference
In-Depth Information
4. PCP IN KIDNEY DEVELOPMENT
Many of the processes proposed to regulate kidney development such
as directed cell migration during UB branching and potentially nephron for-
mation, CE movements during tubule diameter establishment, and oriented
cell division during elongation depend on PCP. Several orthologs of the
PCP determinants are expressed in the developing kidney. Characterization
of mouse kidneys mutated for these factors has uncovered a number of de-
fects, some expected and some unexpected. In many cases, the defects have
not been attributed to any specific deficit in PCP. On the other hand, several
mutants have recently been found to have defects in some aspects of PCP.
In many of these cases, it is not clear how the genes affected relate to the
establishment of PCP. In this section, we describe our current understanding
of the role of all types of PCP during kidney development.
4.1. The Fat/Ds group
4.1.1 Branching morphogenesis
There are four mammalian paralogs of
Fat
(
Fat1-4
) and two orthologs of
Ds
(
Dchs1
and
Dchs2
). Although
Fat4
has the highest overall degree of similarity
to Drosophila Fat, the other three paralogs show conservation in important
functional regions (
Matakatsu & Blair, 2012
).
Kidneys lacking
Dchs1
show mild defects in early UB branching mor-
phogenesis, resulting in kidneys that are reduced in size (
Mao et al.,
2011
).
Fat4
mutants show a very similar phenotype, suggesting that the
interaction between Fat and Dachsous proteins is conserved in mice
(
Mao et al., 2011
). Indeed, compound heterozygotes show phenotypes
nearly identical to the individual homozygotes, further supporting an inter-
action (
Mao et al., 2011
).
The precise causes of the defects leading to reduced branching in these
mutants are unclear. Both show increased rates of apoptosis within the ureteric
bud and decreased rates of proliferation within the nephron progenitors and
the UB. These sorts of changes on cell number are not typically associated
with defects in PCP. Indeed, no specific defects in PCP were identified in
mutants during branching morphogenesis although there are clear defects dur-
ing tubule elongation (see below). Interestingly,
Fat4
and
Dchs1
proteins are
present at high levels in the interstitiumwith lower levels in the nephron pro-
genitors. Levels are very low to undetectable in the ureteric bud (
Mao et al.,
2011
). Thus, it is possible that
Fat4
and
Dchs1
regulate an unknown PCP in
