Kidney
Defects in Mutant Animals
Last revision – 9th
July 2009
This
table is part of the Kidney Development
Database.
It concentrates on kidney defects which are
'developmental' in
character and is not intended to include later pathologies
created through
primary lesions in other systems. For example, mutations that unbalance
the
immune system and create
glomerulonephritic kidney damage are not included.
List of mutant tables (or just scroll);
Mutations affecting
the embryo’s
ability to form an MM at all.
Mutations
affecting ureteric
bud/collecting duct (see later table for mature ureter)
|
Gene |
Mutant type |
Phenotype |
Reference |
|
Agtr2 |
Knockout |
Duplicated
collecting system, abnormal ureteric budding |
Oshima
(2001) |
|
Alk3 |
Floxed
Alk3, HoxB7cre-EGFP |
Abnormal
primary branch pattern, excess subsequent branching at first but then
it reduces dramatically (to below normal). Hypoplastic medulla;
abnormal expression of b-catenin and myc in medullary coll duct. |
Hartwig S
(2008) |
|
Bcl2 |
Knockout
and HoxB7-knock-in rescue |
Branching
defect in knockout; rescued if bcl2 is re-expressed only in ub. |
Kondo
(2008) |
|
Dlgh1 |
Knockout |
Ectopic
ureteric buds, hypoplastic kidneys |
Iizuka-Kogo
(2007) |
|
Emx2 |
Knockout |
UB forms
but its tip never dilates, branching fails to happen |
Miyamoto
(1997) See also Pellgerini
(1996) |
|
Eya1 |
Knockout
and hypomorphs |
Failure of
ub formation (secondary to problems in the MM so no GDNF made). UB
formation but no branching in hypomorphs that yield 20% normal Eya1
levels |
Sajithlal
(2005) |
|
FGF7 |
Knockout |
kidneys
smaller than +/+ wt; affecting both coll duct system size and nerhron
number |
Qiao
(1999) |
|
FgfR1 |
Floxed
fgfr1, floxed fgfr2, Pax3-cre |
Ub forms
but does not elongate or branch (but does express Ret and Pax2 normally) |
Poladia
(2006) |
|
Fgfr2 |
Conditional |
Ectopic
buds |
Hains
(2008) |
|
Fgfr2 |
knockout |
Mis-patterned
UB tree; too few tips |
Zhao (2004) |
|
FoxC1 |
Knockout |
Ectopic
and duplex buds; gdnf region too anterior |
Kume (2000) |
|
FoxD1
(=BF2) |
knockout |
hypoplastic;
fused; c.d. small; too few nephrons; large mesenchymal condensates
(Hatini) Mis-patterned UB tree, probably a tertiary effect of gene loss
causing failure of capsule formation and consequent failure of
organization of BMP4-expressing
mesenchymal cells that normally help pattern UB. (Levinson) |
Hatini
(1996) Levinson
(2005) |
|
Fused mutation |
Random |
Variable
failure of UB growth |
Theiler
(1956) |
|
Gata2 |
Hypomorph |
Anteriorly-displaced
ureteric budding and reduced BMP4 in intermediate mesenchyme
derivatives. |
Hoshino
(2008) |
|
Gata3 |
floxed
gata3, HoxB7 cre |
Multiple
ectopic buds; some duplex kidneys, other defects. Phenotype may depend
on FGF signalling |
Grote
(2008) |
|
GDNF |
heterozygote |
30% fewer
neprhons; reduced extent of ureteric bud. |
Cullen-McEwen
(2001) |
|
GDNF |
knockout |
renal
agenesis due to lack of ureteric bud; can be rescued in vitro by added GDNF |
Sanchez
(1996) Pichel
(1996) Sainio
(1997) |
|
Glypican3 |
Heterozygote
in various heterozygotes of BMP pathway components |
Reduction
of Gpc3 increases UB cell proliferation, probably due to reduced BMP
sigalling |
Hartwig
(2005) |
|
Gremlin |
knockout |
Over-high
pSmad in MM, GDNF/Wnt11 loop not set up properly, ureteric
outgrowth fails. Phenoptype is recuable by genetic reduction of BMP4 |
Michos
(2007) |
|
Hs2ost |
Knockout |
no
branching of ub; no condensation of mesenchyme |
Bullock
(1998) |
|
ICAT
(=ctnnbip1) |
Knockout |
Delayed ub
branching, then arrest of ub branching; renal agenesis |
Hasegawa Y
(2007) |
|
Integrin
alpha 3 |
knockout |
too few
collecting duct branches; cystic proximal tubules |
Kreidberg
(1996) |
|
Integrin
alpha 8 |
knockout |
failure of
ureteric bud growth; nephrons do not epithelialize |
Muller
(1997) |
|
Ld (limb
deformity mutation – affects formins) |
random |
variable
failure of ureteric bud growth |
|
|
Lgl1 |
heterozygote |
20%
reduction in ureteric bud branching |
Quinlan J
(2007) |
|
Lim1 |
Floxed
Lim1, Pax2 cre |
Formation
of Ub delayed, ub branches too little and grows too little. WD dies
back, MD fails even in females. Renal hypoplasia, hydronephrosis |
Pedersen
(2005) Also see
Kobayashi (2005) |
|
Met |
floxed
Met, HoxB7 cre |
Branching
defect (too few), can be rescued partially by EGF |
Ishibe
(2009) |
|
Nephronectin |
Knockout |
UB
delayed; renal agenesis/ hypoplasia; GDNF reduced dramatically (like
alpha 8 integrin mutants) |
Linton
(2007) |
|
N-myc |
Hypomorph |
Collecting
duct system hypoplasia |
Bates
(2000) |
|
R-cadherin |
knockout |
Odd
morphology, elevated apoptosis |
Dahl (2002) |
|
Ret |
knockout |
variable
failure of ureteric bud invasion, growth & branching; MM can still
be induced by spinal cord. |
Pachnis
(1993) Schuchardt
(1994) |
|
Ret
overexpression |
driven by
hox b7promoter (= expression throughout bud) |
variable
failure of ureteric bud growth & branching. (see paper - this
summary is way too brief) |
Srinivas
(1999) |
|
Retinoic
acid receptor (RAR) alpha / beta 1 |
Double
knockout |
impaired
stromal function; poor ub branching. c-Ret down-regulated. |
Mendelsohn
(1999) Batourina
(2001) |
|
Robo2 |
Knockout |
Supernumerary
buds, possibly because GDNF is maintained in appropriately anteriorly |
Grieshammer
(2004) |
|
Sall1 |
Knockout |
MM fails
to attract UB |
Nishinakamura
(2001) |
|
Sd
(Danforth’s short tail) mutation |
random |
hypoplastic/aplastic
kidneys (ureteric bud invasion inhibited |
Gluecksohn-Schoenheimer
(1943) |
|
Slit2 |
Knockout |
Supernumerary
buds, possibly because GDNF is maintained in appropriately anteriorly |
Grieshammer
(2004) |
|
Sprouty1 |
knockout |
Supernumerary
buds, Irregular ub branching; tips larger and more numerous than
controls. Increased wnt11 and gdnf expression. Cystic hyperplasia |
Basson
(2006) |
|
TGFb |
heterozygote |
Extra
generation of branches and longer branches |
Sims-Lucas
(2008) |
|
Wg
(chicken wingless – is NOT connected to Drosophila Wg!) |
random |
Failure of
ureteric bud invasion |
secondary
source:Ede 1978 -anyone know the primary source? (please mail me) |
|
Wnt11 |
knockout |
Too little
ub branching; renal hypoplasia; GDNF levels too low |
Majumdar A
(2003) |
Mutations affecting
the behaviour
of MM, cap condensates and pre-tubular aggregates.
|
Gene |
Mutant type |
Phenotype |
Reference |
|
FgfR1 |
Floxed
fgfr1, floxed fgfr2, Pax3-cre |
Too much
apoptosis and too little proliferation in MM. Six2, Pax2, Sall1 no
activated (but Eya1 and Six1 are) |
Poladia
(2006) |
|
Hs2ost |
Knockout |
no
branching of ub; no condensation of mesenchyme |
Bullock
(1998) |
|
Integrin
alpha 8 |
knockout |
nephrons
do not epithelialized (and ub fails to grow properly) |
Muller
(1997) |
|
P53
over-expression |
overexpression |
hypoplastic;
defective collecting duct diffn; high apoptosis of nephrogenic
mesenchyme; 'inefficient conversion to tubules |
Godley
(1996) |
|
R-cadherin |
knockout |
Fewer
tubules form |
Dahl (2002) |
|
Sall1 |
Knockout |
MM fails
to attract UB |
Nishinakamura
(2001) |
|
Six2 |
knockout |
Too much
nephrogenesis at the expense of stem cell maintenance: cap mesenchyme
lost as it all becomes nephrons |
Self (2006) |
|
Shh |
Knockout |
MM dies |
Yu (2002) |
|
Wnt4 |
knockout |
Pretubular
aggregates do not form (or form in very low numbers) |
Stark
(1994) See also
Kispert (1998) |
|
Wt1 |
Knockout |
MM cannot
form nephrons, nor support bud growth, nor survive. |
Kreidberg
(1993) |
|
Wt1 |
siRNA
inhibition |
MM
proliferates in response to ub but does not differentiate into nephrons |
Davies
(2004) |
Mutations
affecting development of
nephron epithelia (Renal vesicle onwards)
|
Gene |
Mutant type |
Phenotype |
Reference |
|
Bmp7 |
knockout |
1. severe
kid hypoplasia (lethal); early devpt OK (->E12.5), but then few
nephrons form and cd branching ceases (Dudley
& Luo) |
Luo (1995) |
|
Cadherin6 |
knockout |
many
nephrons fail to fuse to the bud |
Mah (2000)
|
|
Epstein-Barr
nuclear antigen 2 |
Transgenic
expression of viral gene |
Tubular
hyperplasia then adenocarcinoma |
Tornell
(1996) |
|
Glucose-6-phosphatase |
knockout |
tubules
enlarge at the expense of glomeruli |
Lei (1996) |
|
HNF1 |
knockout |
Fanconi
syndrome (proximal tubule dysfunction) during post-natal devt |
Pontoglio
(1996) |
|
Lim1 |
Floxed
Lim1, Rarb2 cre |
Nephrons
arrest at renal vesicle |
Kobayashi
(2005) |
|
MALS-3 |
|
Apico-basal
polarity defects especially in proximal tubules. Reflected in
mislocation of |
Olsen
(2007) |
Mutations
affecting glomerular
development (but later than the formation of a renal vesicle).
|
Gene |
Mutant type |
Phenotype |
Reference |
|
Collagen
IV alpha 3 |
Knockout |
Alport’s
syndrome |
Cosgrove
(1996) |
|
Lmx1b |
Knockout |
Podocytes
start to form but their foot processes are soon lost. |
Witzgall
(2008) |
|
Notch 2
(del1 allele) |
knockout |
McRight
(2001) |
|
|
Notch 2
(del1 allele) Jag-1 (dDSL allele) |
double
heterozygote |
McRight
(2001) |
|
|
Uteroglobin |
Knockout |
FN-deposit
glomerular disease |
Zhang 1997 |
Mutations affecting mainly
vasculature
|
Gene |
Mutant type |
Phenotype |
Reference |
|
Angiotensinogen |
knockout |
Vessel
walls thicken during post-natal development |
Kim (1995) |
|
Gs-alpha (part of
adenylyl cyclase pathway) |
Floxed
GsAlpha, Ren1d cre |
Renin
expression absent; some differences in modelling of pre-glomerular
arterial tree |
Neubaueer
(2009) |
|
PDGFb |
Knockout |
Very few
glomeruli; absence of mesangial cells |
Lindahl
(1998) |
|
PDGFR |
Knockout |
No
mesangial cells, probably because mesenchyme migration to PDGF sources
messed up. |
Ricono
(2009) |
|
Gene |
Mutant type |
Phenotype |
Reference |
|
Bcl2-/- |
knockout |
polycystic
disease; hypoplasia due to excess apoptosis during abnormal
neprhogenesis |
Veis (1993) Nagata
(1996) |
|
Bmp4 |
heterozygote |
polycystic
during post-natal devt (Dunn) |
Dunn (1997) |
|
Dicer |
floxed
dicer, HoxB7cre |
Cysts
(collecting duct and nephron derived) |
Pastorelli
(2009) |
|
FGF7 |
Overexpression
in LIVER (not kidney) |
kidneys
smaller than +/+ wt; affecting both coll duct system size and nerhron
number |
Nguyen
(1996) |
|
Glypican-3 |
Knockout |
Cystic
collecting ducts |
Cano-Gauci
(1999) |
|
Integrin
alpha 3 |
knockout |
too few
collecting duct branches; cystic proximal tubules |
Kreidberg
(1996) |
|
Inv mutant |
random |
Cystic
kidneys |
Mochizuki
(1998) |
|
MALS-3 |
|
Apico-basal
polarity defects especially in proximal tubules. Reflected in
mislocation of |
Olsen
(2007) |
|
Sprouty1 |
knockout |
Irregular
ub branching; tips larger and more numerous than controls. Increased
wnt11 and gdnf expression. Cystic hyperplasia |
Basson
(2006) |
Mutations
affecting ureter (&
connection to bladder):
|
Gene |
Mutant type |
Phenotype |
Reference |
|
BMP4 |
Floxed BMP4 |
Poor
ureteric muscle development, ureteropelvic junction obstruction |
Wang 2008 |
|
Dlgh1 |
Knockout |
Wrongly
orientated ureteric muscles, impaired peristalsis. |
Mahoney
(2006) |
|
Nfia |
Knockout
and heterozygote |
Abnormalities
of uretopelvic junction and uretovesical junction, megaureter |
Lu (2007) |
|
Ptprs,
Ptprf double mutant |
knockout |
Hydroureter,
ureterocoele, possibly due to abnormally low cell death during
morphogenesis: Ptprs inhibits Ret signalling |
Uetani
(2009) |
|
Tbx18 |
Knockout |
Cells that
should have been mesenchyme of ureter mislocate to surface of kidney;
ones that remain don’t make muscle but make fibrous or ligamentous
tissue instead. Short ureter; hydronephrosis. |
Airik
(2006) |
|
Tshz3 |
Knockout |
Congenital
hydronephrosis presumed due to absence of proximal smooth muscle cells |
Caubit
(2008) |
|
Gene |
Mutant type |
Phenotype |
Reference |
|
ACE |
Knockout |
Cortical
thinning and atrophy in adulthood |
Krege
(1995) |
|
AP-2 |
knockout |
hypoplastic;
retarded devt of metanephros; many other defects in embryo |
Zhang 1996 |
|
|
knockout |
poor bud
devt apparent by birth; nephrons few and immature (E14 kidneys look OK ) |
Dinchuk
(1995) |
|
FGF-R
dominant negative - blocks aFGF, FGF3 & 7 not
bFGF or FGF4 |
transgenic |
no
kidneys, or very small ones with vacuolated tubules |
Celli
(1998) |
|
Hexb |
Knockout |
vacuolation
during post-natal devt |
Phaneuf
(1996) |
|
Os
(oligosyndactly) |
Heterzygote |
hypoplasia
in vivo & in culture |
Sorenson
(1996) |
|
P57 |
Knockout |
Zhang
(1997) |