The metanephric kidney develops from interactions between the epithelial ureteric bud and adjacent metanephric mesenchyme, which is induced by the bud to form the epithelia of the nephron. We have found that leukemia inhibitory factor (LIF) and transforming growth factor beta 2 (TGF beta 2) are secreted by inductive rat bud cells and cooperate to enhance and accelerate renal tubule formation in uninduced rat metanephric mesenchymal explants. LIF alone or TGF beta 2 with fibroblast growth factor 2 induced numerous tubules in isolated mesenchymes over an 8 day period, while (in combination) all three caused abundant tubule formation in 72 hours. Furthermore, neutralization of Wnt ligands with antagonist-secreted Frizzled-related protein 1 abrogated these responses and combinatorial cytokine/growth factor stimulation of explants augmented nuclear activation of Tcf1/Lef1, suggesting that LIF and TGF beta 2/FGF2 cooperate to regulate nephrogenesis through a common Wnt-dependent mechanism.

Reference

Armes
N. A.
,
Smith
J. C.
(
1997
)
The ALK-2 and ALK-4 activin receptors transduce distinct mesoderm-inducing signals during early Xenopus development but do not co-operate to establish thresholds.
Development
124
,
3797
3804
Aubert
J.
,
Dessolin
S.
,
Belmonte
N.
,
Li
M.
,
McKenzie
F. R.
,
Staccini
L.
,
Villageois
P.
,
Barhanin
B.
,
Vernallis
A.
,
Smith
A. G.
, et al. 
(
1999
)
Leukemia inhibitory factor and its receptor promote adipocyte differentiation via the mitogen-activated protein kinase cascade.
J. Biol. Chem
274
,
24965
24972
Austin
L.
,
Bower
J.
,
Kurek
J.
,
Vakakis
N.
(
1992
)
Effects of leukaemiainhibitory factor and other cytokines on murine and human myoblast proliferation.
J. Neurol.Sci
112
,
185
191
Bafico
A.
,
Gazit
A.
,
Pramila
T.
,
Finch
P. W.
,
Yaniv
A.
,
Aaronson
S. A.
(
1999
)
Interaction of frizzled related protein (FRP) with Wnt ligands and the frizzled receptor suggests alternative mechanisms for FRP inhibition of Wnt signaling.
J. Biol. Chem
274
,
16180
16187
Barasch
J.
,
Qiao
J.
,
McWilliams
G.
,
Chen
D.
,
Oliver
J. A.
,
Herzlinger
D.
(
1997
)
Ureteric bud cells secrete multiple factors, including bFGF, which rescue renal progenitors from apoptosis.
Am. J. Physiol
273
,
757
–.
Barasch
J.
,
Yang
J.
,
Ware
C. B.
,
Taga
T.
,
Yoshida
K.
,
Erdjument-Bromage
H.
,
Tempst
P.
,
Parravicini
E.
,
Malach
S.
,
Aranoff
T.
,
Oliver
J. A.
(
1999
)
Mesenchymal to epithelial conversion in rat metanephros is induced by LIF.
Cell
99
,
377
386
Bard
J. B. L.
,
Ross
A. S. A.
(
1991
)
LIF, the ES-cell inhibition factor, reversibly blocks nephrogenesis in cultured mouse kidney rudiments.
Development
113
,
193
198
Boccaccio
C.
,
Ando
M.
,
Tamagnone
L.
,
Bardelli
A.
,
Michieli
P.
,
Battistini
C.
,
Comoglio
P. M.
(
1998
)
Induction of epithelial tubules by growth factor HGF depends on the STAT pathway.
Nature
391
,
285
288
Bonewald
L. F.
,
Wakefield
L.
,
Oreffo
R. O.
,
Escobedo
A.
,
Twardzik
D. R.
,
Mundy
G. R.
(
1991
)
Latent forms of transforming growth factor-(TGF-) derived from bone cultures: identification of a naturally occurring 100-kDa complex with similarity to recombinant latent TGF.
Mol Endocrinol
5
,
741
751
Crease
D. J.
,
Dyson
S.
,
Gurdon
J. B.
(
1998
)
Cooperation between the activin and Wnt pathways in the spatial control of organizer gene expression.
Proc. Natl. Acad. Sci. USA
95
,
4398
4403
Dignam
J. D.
,
Martin
P. L.
,
Shastry
B. S.
,
Roeder
R. G.
(
1983
)
Eukaryotic gene transcription with purified components.
Methods Enzymol
101
,
582
598
Dressler
G. R.
,
Wilkinson
J. E.
,
Rothernpieler
U. W.
,
Patterson
L. T.
,
Williams-Simons
L.
,
Westphal
H.
(
1993
)
Deregulation of Pax-2 expression in transgenic mice generates severe kidney abnormalities.
Nature
362
,
65
67
Dudley
A. T.
,
Godin
R. E.
,
Robertson
E. J.
(
1999
)
Interaction between FGF and BMP signaling pathways regulates development of metanephric mesenchyme.
Genes Dev
13
,
1601
1613
Elias
J. A.
,
Zheng
T.
,
Whiting
N. L.
,
Marcovici
A.
,
Trow
T. K.
(
1994
)
Cytokine-cytokine synergy and protein kinase C in the regulation of lung fibroblast leukemia inhibitory factor.
Am. J. Physiol
266
,
426
–.
Feng
X. H.
,
Zhang
Y.
,
Wu
R. Y.
,
Derynck
R.
(
1998
)
The tumor suppressor Smad4/DPC4 and transcriptional adaptor CBP/p300 are coactivators for smad3 in TGF--induced transcriptional activation.
Genes Dev
12
,
2153
2163
Finch
P. W.
,
He
X.
,
Kelley
M. J.
,
Uren
A.
,
Schaudies
R. P.
,
Popescu
N. C.
,
Rudikoff
S.
,
Aaronson
S. A.
,
Varmus
H. E.
,
Rubin
J. S.
(
1997
)
Purification and molecular cloning of a secreted, Frizzled-related antagonist of Wnt action.
Proc. Natl. Acad. Sci. USA
94
,
6770
6775
Gendron
R. L.
,
Tsai
F. Y.
,
Paradis
H.
,
Arceci
R. J.
(
1996
)
Induction of embryonic vasculogenesis by bFGF and LIF in vitro and in vivo.
Dev. Biol
177
,
332
346
Gibson
S.
,
Tu
S.
,
Oyer
R.
,
Anderson
S. M.
,
Johnson
G. L.
(
1999
)
Epidermal growth factor protects epithelial cells against Fas-induced apoptosis.
J. Biol. Chem
274
,
17612
17618
Grobstein
C.
(
1953
)
Morphogenetic interaction between embryonic mouse tissues separated by a membrane filter.
Nature
172
,
859
871
Gruenwald
P.
(
1943
)
Stimulation of nephrogenic tissues by normal and abnormal inductors.
Anat. Rec
86
,
321
335
Hartner
A.
,
Sterzel
R. B.
,
Reindl
N.
,
Hocke
G. M.
,
Fey
G. H.
,
Goppelt-Struebe
M.
(
1994
)
Cytokine-induced expression of leukemia inhibitory factor in renal mesangial cells.
Kidney Int
45
,
1562
1571
Hecht
A.
,
Vleminckx
K.
,
Stemmler
M. P.
,
van Roy
F.
,
Kemler
R.
(
2000
)
The p300/CBP acetyltransferases function as transcriptional coactivators of-catenin in vertebrates.
EMBO J
19
,
1839
1850
Heim
M. H.
(
1999
)
The Jak-STAT pathway: cytokine signalling from the receptor to the nucleus.
J. Recept. Signal Transduct. Res
19
,
75
120
Karavanov
A. A.
,
Karavanova
I.
,
Perantoni
A.
,
Dawid
I. B.
(
1998
)
Expression pattern of the rat Lim-1 homeobox gene suggests a dual role during kidney development.
Int. J. Dev. Biol
42
,
61
66
Karavanova
I. D.
,
Dove
L. F.
,
Resau
J. H.
,
Perantoni
A. O.
(
1996
)
Conditioned medium from a rat ureteric bud cell line in combination withbFGF induces complete differentiation of isolated metanephric mesenchyme.
Development
122
,
4159
4167
Kispert
A.
,
Vainio
S.
,
McMahon
A. P.
(
1998
)
Wnt-4 is a mesenchymal signal for epithelial transformation of metanephric mesenchyme in the developing kidney.
Development
125
,
4225
4234
Knight
D. A.
,
Lydell
C. P.
,
Zhou
D.
,
Weir
T. D.
,
Robert
S. R.
,
Bai
T. R.
(
1999
)
Leukemia inhibitory factor (LIF) and LIF receptor in human lung. Distribution and regulation of LIF release.
Am. J. Respir. Cell Mol. Biol
20
,
834
841
Koblar
S. A.
,
Turnley
A. M.
,
Classon
B. J.
,
Reid
K. L.
,
Ware
C. B.
,
Cheema
S. S.
,
Murphy
M.
,
Bartlett
P. F.
(
1998
)
Neural precursor differentiation into atrocytes requires signaling through the leukemia inhibitory factor receptor.
Proc. Natl. Acad. Sci. USA
95
,
3178
3181
Korinek
V.
,
Barker
N.
,
Morin
P. J.
,
van Wichen
D.
,
de Weger
R.
,
Kinzler
K. W.
,
Vogelstein
B.
,
Clevers
H.
(
1997
)
Constitutive transcriptional activation by a-catenin-Tcf complex in APC−/−colon carcinoma.
Science
275
,
1784
1787
Koseki
C.
(
1993
)
Cell death programmed in uninduced metanephric mesenchymal cells.
Pediatr. Nephrology
7
,
609
611
Kreidberg
J. A.
,
Sariola
H.
,
Loring
J. M.
,
Maeda
M.
,
Pelletier
J.
,
Housman
D.
,
Jaenisch
R.
(
1993
)
WT1 is required for early kidney development.
Cell
74
,
679
691
Krieglstein
K.
,
Farkas
L.
,
Unsicker
K.
(
1998
)
TGF-beta regulates the survival of ciliary ganglionic neurons synergistically with ciliary neurotrophic factor and neurotrophins.
J. Neurobiol
37
,
563
572
Lescher
B.
,
Haenig
B.
,
Kispert
A.
(
1998
)
sFRP-2 is a target of the Wnt-4 signaling pathway in the developing metanephric kidney.
Dev. Dyn
213
,
440
451
Mariano
J. M.
,
Montuenga
L. M.
,
Prentice
M. A.
,
Cuttitta
F.
,
Jakowlew
S. B.
(
1998
)
Concurrent and distinct transcription and translation of transforming growth factor-type I and type II receptors in rodent embryogenesis.
Int. J. Dev. Biol
42
,
1125
1136
Massague
J.
(
1998
)
TGF-signal transduction.
Annu. Rev. Biochem
67
,
753
791
Matsuoka
I.
,
Nakane
A.
,
Kurihara
K.
(
1997
)
Induction of LIF-mRNA by TGF-beta 1 in Schwann cells.
Brain Res
776
,
170
180
Mayer
M.
,
Bhakoo
K.
,
Noble
M.
(
1994
)
Ciliary neurotrophic factor and leukemia inhibitory factor promote the generation, maturation and survival of oligodendrocytes in vitro.
Development
120
,
143
153
McPherron
A. C.
,
Lawler
A. M.
,
Lee
S. J.
(
1999
)
Regulation of anterior/posterior patterning of the axial skeleton by growth/differentiation factor 11.
Nat. Genet
22
,
260
264
Megeney
L. A.
,
Perry
R. L.
,
LeCouter
J. E.
,
Rudnicki
M. A.
(
1996
)
bFGF and LIF signaling activates STAT3 in proliferating myoblasts.
Dev. Genet
19
,
139
145
Nakashima
K.
,
Yanagisawa
M.
,
Arakawa
H.
,
Kimura
N.
,
Hisatsune
T.
,
Kawabata
M.
,
Miyazono
K.
,
Taga
T.
(
1999
)
Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300.
Science
284
,
479
482
Nishita
M.
,
Hashimoto
M. K.
,
Ogata
S.
,
Laurent
M. N.
,
Ueno
N.
,
Shibuya
H.
,
Cho
K. W. Y.
(
2000
)
Interaction between Wnt and TGF-signalling pathways during formation of Spemann's organizer.
Nature
403
,
781
785
O'Reilly
M. A.
,
Danielpour
D.
,
Roberts
A. B.
,
Sporn
M. B.
(
1992
)
Regulation of expression of transforming growth factor-2 by transforming growth factor- isoforms is dependent upon cell type.
Growth Factors
6
,
193
201
Oosterwegel
M.
,
van de
W. M.
,
Timmerman
J.
,
Kruisbeek
A.
,
Destree
O.
,
Meijlink
F.
,
Clevers
H.
(
1993
)
Differential expression of the HMG box factors TCF-1 and LEF-1 during murine embryogenesis.
Development
118
,
439
448
Oosterwijk
E.
,
Van Muijen
G. N.
,
Oosterwijk-Wakka
J. C.
,
Warnaar
S. O.
(
1990
)
Expression of intermediate-sized filaments in developing and adult human kidney and in renal cell carcinoma.
J. Histochem. Cytochem
38
,
385
392
Pedrozo
H. A.
,
Schwartz
Z.
,
Robinson
M.
,
Gomes
R.
,
Dean
D. D.
,
Bonewald
L. F.
,
Boyan
B. D.
(
1999
)
Potential mechanisms for the plasmin-mediated release and activation of latent transforming growth factor-1 from the extracellular matrix of growth plate chondrocytes.
Endocrinology
140
,
5806
5816
Pelton
R. W.
,
Saxena
B.
,
Jones
M.
,
Moses
H. L.
,
Gold
L. I.
(
1991
)
Immunohistochemical localization of TGF1, TGF 2, and TGF3 in the mouse embryo: expression patterns suggest multiple roles during embryonic development.
J. Cell Biol
115
,
1091
1105
Perantoni
A. O.
,
Kan
F. W. K.
,
Dove
L. F.
,
Reed
C. D.
(
1985
)
Selective growth in culture of fetal rat renal collecting duct anlagen.
Lab. Invest
53
,
589
596
Perantoni
A. O.
,
Dove
L. F.
,
Williams
C. L.
(
1991
)
Induction of tubules in rat metanephrogenic mesenchyme in the absence of inductive tissue.
Differentiation
48
,
25
31
Perantoni
A. O.
,
Williams
C. L.
,
Lewellyn
A. L.
(
1991
)
Growth and branching morphogenesis of rat collecting duct anlagen in the absence of metanephrogenic mesenchyme.
Differentiation
48
,
107
113
Perantoni
A. O.
,
Dove
L. F.
,
Karavanova
I.
(
1995
)
Basic fibroblast growth factor can mediate the early inductive events in renal development.
Proc. Natl. Acad. Sci. USA
92
,
4696
4700
Ritvos
O.
,
Tuuri
T.
,
Eramaa
M.
,
Sainio
K.
,
Hilden
K.
,
Saxen
L.
,
Gilbert
S. F.
(
1995
)
Activin disrupts epithelial branching morphogenesis in developing glandular organs of the mouse.
Mech. Dev
50
,
229
245
Rogers
S. A.
,
Ryan
G.
,
Purchio
A. F.
,
Hammerman
M. R.
(
1993
)
Metanephric transforming growth factor-1 regulates nephrogenesis in vitro.
Am. J. Physiol
264
,
996
1002
Roose
J.
,
Huls
G.
,
van Beest
M.
,
Moerer
P.
,
van der
H. K.
,
Goldschmeding
R.
,
Logtenberg
T.
,
Clevers
H.
(
1999
)
Synergy between tumor suppressor APC and the-catenin-Tcf4 target Tcf1.
Science
285
,
1923
1926
Sanford
L. P.
,
Ormsby
I.
,
Gittenberger-de Groot
A. C.
,
Sariola
H.
,
Friedman
R.
,
Boivin
G. P.
,
Cardell
E. L.
,
Doetschman
T.
(
1997
)
TGF2 knockout mice have multiple developmental defects that are non-overlapping with other TGF knockout phenotypes.
Development
124
,
2659
2670
Satoh
M.
,
Sugino
H.
,
Yoshida
T.
(
2000
)
Activin promotes astrocytic differentiation of a multipotent neural stem cell line and an astrocyte progenitor cell line from murine central nervous system.
Neurosci. Lett
284
,
143
146
Saxen
L.
,
Lehtonen
E.
(
1978
)
Transfilter induction of kidney tubulesas a function of the extent and duration of intercellular contacts.
J. Embryol. Exp. Morphol
47
,
97
109
Shawlot
W.
,
Behringer
R. K.
(
1995
)
Requirement of Lim1 in head-organizer function.
Nature
374
,
425
430
Stark
K.
,
Vainio
S.
,
Vassileva
G.
,
McMahon
A. P.
(
1994
)
Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4.
Nature
372
,
679
683
Stefana
B.
,
Ray
D. W.
,
Melmed
S.
(
1996
)
Leukemia inhibitory factor induces differentiation of pituitary corticotroph function: an immuno-neuroendocrine phenotypic switch.
Proc Natl. Acad Sci USA
93
,
12502
12506
Stewart
C. L.
,
Kaspar
P.
,
Brunet
L. J.
,
Bhatt
H.
,
Gadi
I.
,
Kontgen
F.
,
Abbondanzo
S. J.
(
1992
)
Blastocyst implantation depends on maternal expression of leukaemia inhibitory factor.
Nature
359
,
76
79
Tomida
M.
(
1997
)
Presence of mRNAs encoding the soluble D-factor/LIF receptor in human choriocarcinoma cells and production of the soluble receptor.
Biochem. Biophys. Res. Commun
232
,
427
431
Vassalli
A.
,
Matzuk
M. M.
,
Gardner
H. A.
,
Lee
K. F.
,
Jaenisch
R.
(
1994
)
Activin/inhibin beta B subunit gene disruption leads to defects in eyelid development and female reproduction.
Genes Dev
8
,
414
427
Vestweber
D.
,
Kemler
R.
,
Ekblom
P.
(
1985
)
Cell-adhesion molecule uvomorulin during kidney development.
Dev. Biol
112
,
213
221
Weller
A.
,
Sorokin
L.
,
Illgen
E. M.
,
Ekblom
P.
(
1991
)
Development and growth of mouse embryonic kidney in organ culture and modulation of development by soluble growth factor.
Dev. Biol
144
,
248
261
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