In C. elegans, the TGFbeta-like type II receptor daf-4 is required for two distinct signaling pathways. In association with the type I receptor daf-1, it functions in the dauer pathway. In addition, it is also required for body size determination and male tail patterning, roles which do not require daf-1. In an effort to determine how two different signals are transmitted through daf-4, we looked for other potential signaling partners for DAF-4. We have cloned and characterized a novel type I receptor and show that it is encoded by sma-6. Mutations in sma-6 generate the reduced body size (Sma) and abnormal mail tail (Mab) phenotypes identical to those observed in daf-4 and sma-2, sma-3, sma-4 mutants (C. elegans Smads), indicating that they function in a common signaling pathway. However, mutations in sma-6, sma-2, sma-3, or sma-4 do not produce constitutive dauers, which demonstrates that the unique biological functions of daf-4 are mediated by distinct type I receptors functioning in parallel pathways. We propose that the C. elegans model for TGFbeta-like signaling, in which distinct type I receptors determine specificity, may be a general mechanism of achieving specificity in other organisms. These findings distinguish between the manner in which signaling specificity is achieved in TGFbeta-like pathways and receptor tyrosine-kinase (RTK) pathways.

Reference

Arora
K.
,
Levine
M. S.
,
O'Connor
M. B.
(
1994
)
The screw gene encodes a ubiquitously expressed member of the TGF-family required for specification of dorsal cell fates in the Drosophila embryo.
Genes Dev
8
,
2588
2601
Attisano
L.
,
Wrana
J. L.
(
1998
)
Mads and Smads in TGFsignalling.
Curr. Opin. Cell Biol
10
,
188
194
Baird
S. E.
,
Fitch
D. H.
,
Kassem
I. A.
,
Emmons
S. W.
(
1991
)
Pattern formation in the nematode epidermis: determination of the arrangement of peripheral sense organs in the C. elegans male tail.
Development
113
,
515
526
Baker
J. C.
,
Harland
R. M.
(
1996
)
A novel mesoderm inducer, Madr2, functions in the activin signal transduction pathway.
Genes Dev
10
,
1880
1889
Brenner
S.
(
1974
)
The genetics of Caenorhabditis elegans.
Genetics
77
,
71
94
Brunner
D.
,
Oellers
N.
,
Szabad
J.
,
Biggs
W. H.
3rd
,
Zipursky
S. L.
,
Hafen
E.
(
1994
)
A gain-of-function mutation in Drosophila MAP kinase activates multiple receptor tyrosine kinase signaling pathways.
Cell
76
,
875
888
Chen
X.
,
Rubock
M. J.
,
Whitman
M.
(
1996
)
A transcriptional partner for MAD proteins in TGF-signalling.
Nature
383
,
691
696
Chen
X.
,
Weisberg
E.
,
Fridmacher
V.
,
Watanabe
M.
,
Naco
G.
,
Whitman
M.
(
1997
)
Smad4 and FAST-1 in the assembly of activin-responsive factor.
Nature
389
,
85
89
Chen
Y.
,
Riese
M. J.
,
Killinger
M. A.
,
Hoffmann
F. M.
(
1998
)
A genetic screen for modifiers of Drosophiladecapentaplegic signaling identifies mutations in punt, Mothers against dpp and the BMP-7 homologue, 60A.
Development
125
,
1759
1768
Childs
S. R.
,
O'Connor
M. B.
(
1994
)
Two domains of the tolloid protein contribute to its unusual genetic interaction with decapentaplegic.
Developmental Biology
162
,
209
220
Chisholm
A.
(
1991
)
Control of cell fate in the tail region of C. elegans by the gene egl-5.
Development
111
,
921
932
Chow
K. L.
,
Emmons
S. W.
(
1994
)
HOM-C/Hox genes and four interacting loci determine the morphogenetic properties of single cells in the nematode male tail.
Development
120
,
2579
2592
Colavita
A.
,
Krishna
S.
,
Zheng
H.
,
Padgett
R. W.
,
Culotti
J. G.
(
1998
)
Pioneer axon guidance by UNC-129, a C. elegans TGF-.
Science
281
,
706
709
Derynck
R.
,
Gelbart
W. M.
,
Harland
R. M.
,
Heldin
C. H.
,
Kern
S. E.
,
Massague
J.
,
Melton
D. A.
,
Mlodzik
M.
,
Padgett
R. W.
,
Roberts
A. B.
,
Smith
J.
,
Thomsen
G. H.
,
Vogelstein
B.
,
Wang
X. F.
(
1996
)
Nomenclature: vertebrate mediators of TGFfamily signals.
Cell
87
,
173
–.
Eppert
K.
,
Scherer
S. W.
,
Ozcelik
H.
,
Pirone
R.
,
Hoodless
P.
,
Kim
H.
,
Tsui
L. C.
,
Bapat
B.
,
Gallinger
S.
,
Andrulis
I. L.
,
Thomsen
G. H.
,
Wrana
J. L.
,
Attisano
L.
(
1996
)
MADR2 maps to 18q21 and encodes a TGF-regulated MAD-related protein that is functionally mutated in colorectal carcinoma.
Cell
86
,
543
552
Estevez
M.
,
Attisano
L.
,
Wrana
J. L.
,
Albert
P. S.
,
Massague
J.
,
Riddle
D. L.
(
1993
)
The daf-4 gene encodes a bone morphogenetic protein receptor controlling C. elegans dauer larva development.
Nature
365
,
644
649
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
Finelli
A. L.
,
Bossie
C. A.
,
Xie
T.
,
Padgett
R. W.
(
1994
)
Mutational analysis of the Drosophila tolloid gene, a human BMP-1 homolog.
Development
120
,
861
870
Fire
A.
(
1992
)
Histochemical techniques for locating Escherichia coli beta-galactosidase activity in transgenic organisms.
Genet. Anal. Tech. Appl
9
,
151
158
Fire
A.
,
Harrison
S. W.
,
Dixon
D.
(
1990
)
A modular set of lacZ fusion vectors for studying gene expression in Caenorhabditis elegans.
Gene
93
,
189
198
Georgi
L. L.
,
Albert
P. S.
,
Riddle
D. L.
(
1990
)
daf-1, a C. elegans gene controlling dauer larva development, encodes a novel receptor protein kinase.
Cell
61
,
635
645
Hahn
S. A.
,
Schutte
M.
,
Hoque
A. T.
,
Moskaluk
C. A.
,
da Costa
L. T.
,
Rozenblum
E.
,
Weinstein
C. L.
,
Fischer
A.
,
Yeo
C. J.
,
Hruban
R. H.
,
Kern
S. E.
(
1996
).
DPC4, A Candidate Tumor Suppressor Gene at Human Chromosome 18q21.1.
Science
271
,
350
353
Hata
A.
,
Lagna
G.
,
Massague
J.
,
Hemmati-Brivanlou
A.
(
1998
)
Smad6 inhibits BMP/Smad1 signaling by specifically competing with the Smad4 tumor suppressor.
Genes Dev
12
,
186
197
Hayashi
H.
,
Abdollah
S.
,
Qiu
Y.
,
Cai
J.
,
Xu
Y. Y.
,
Grinnell
B. W.
,
Richardson
M. A.
,
Topper
J. N.
,
Gimbrone
M. A.
Jr.
,
Wrana
J. L.
,
Falb
D.
(
1997
)
The MAD-related protein Smad7 associates with theTGF receptor and functions as an antagonist of TGFsignaling.
Cell
89
,
1165
1173
Heldin
C. H.
,
Miyazono
K.
,
ten Dijke
P.
(
1997
)
TGF-signalling from cell membrane to nucleus through SMAD proteins.
Nature
390
,
465
471
Hoodless
P. A.
,
Haerry
T.
,
Abdollah
S.
,
Stapleton
M.
,
O'Connor
M. B.
,
Attisano
L.
,
Wrana
J. L.
(
1996
)
MADR1, a MAD-related protein that functions in BMP2 signaling pathways.
Cell
85
,
489
500
Imamura
T.
,
Takase
M.
,
Nishihara
A.
,
Oeda
E.
,
Hanai
J.
,
Kawabata
M.
,
Miyazono
K.
(
1997
)
Smad6 inhibits signalling by the TGF-superfamily.
Nature
389
,
622
626
Irish
V. F.
,
Gelbart
W. M.
(
1987
)
The decapentaplegic gene is required for dorsal-ventral patterning of the Drosophila embryo.
Genes Dev
1
,
868
879
Janknecht
R.
,
Wells
N. J.
,
Hunter
T.
(
1998
)
TGF--stimulated cooperation of Smad proteins with the coactivators CBP/p300.
Genes Dev
12
,
2114
2119
Khalsa
O.
,
Yoon
J. W.
,
Torres-Schumann
S.
,
Wharton
K. A.
(
1998
)
TGF-/BMP superfamily members, Gbb-60A and Dpp, cooperate to provide pattern information and establish cell identity in the Drosophila wing.
Development
125
,
2723
2734
Kim
J.
,
Johnson
K.
,
Chen
H. J.
,
Carroll
S.
,
Laughon
A.
(
1997
)
Drosophila Mad binds to DNA and directly mediates activation of vestigial by Decapentaplegic.
Nature
388
,
304
308
Kipreos
E. T.
,
Lander
L. E.
,
Wing
J. P.
,
He
W. W.
,
Hedgecock
E. M.
(
1996
)
cul-1 is required for cell cycle exit in C. elegans and identifies a novel gene family.
Cell
85
,
829
839
Kretzschmar
M.
,
Liu
F.
,
Hata
A.
,
Doody
J.
,
Massague
J.
(
1997
)
The TGF-family mediator Smad1 is phosphorylated directly and activated functionally by the BMP receptor kinase.
Genes Dev
11
,
984
995
Lagna
G.
,
Hata
A.
,
Hemmati-Brivanlou
A.
,
Massague
J.
(
1996
)
Partnership between DPC4 and SMAD proteins in TGF-beta signalling pathways.
Nature
383
,
832
836
Liu
F.
,
Hata
A.
,
Baker
J. C.
,
Doody
J.
,
Cárcamo
J.
,
Harland
R. M.
,
Massague
J.
(
1996
)
A human Mad protein acting as a BMP-regulated transcriptional activator.
Nature
381
,
620
623
Liu
F.
,
Ventura
F.
,
Doody
J.
,
Massague
J.
(
1995
)
Human type II receptor for bone morphogenic proteins (BMPs): extension of the two-kinase receptor model to the BMPs.
Mol. Cell. Biol
15
,
3479
386
Macías-Silva
M.
,
Abdollah
S.
,
Hoodless
P. A.
,
Pirone
R.
,
Attisano
L.
,
Wrana
J. L.
(
1996
)
MADR2 is a substrate of the TGFreceptor and its phosphorylation is required for nuclear accumulation and signaling.
Cell
87
,
1215
1224
Madhani
H. D.
,
Fink
G. R.
(
1998
)
The riddle of MAP kinase signaling specificity.
Trends Genet
14
,
151
155
Massague
J.
(
1998
)
TGFSignal Transduction.
Annu. Rev. Biochem
67
,
753
791
Mello
C. C.
,
Kramer
J. M.
,
Stinchcomb
D.
,
Ambros
V.
(
1991
)
Efficient gene transfer in C. elegans: extrachromosomal maintenance and integration of transforming sequences.
EMBOJ
10
,
3959
70
Miyazono
K.
,
Ten Dijke
P.
,
Ichijo
H.
,
Heldin
C. H.
(
1994
)
Receptors for transforming growth factor-beta.
Adv. Immunol
55
,
181
220
Nakao
A.
,
Afrakhta
M.
,
Moren
A.
,
Nakayama
T.
,
Christian
J. L.
,
Heuchel
R.
,
Itoh
S.
,
Kawabata
M.
,
Heldin
N.-E.
,
Heldin
C.-H.
,
Dijke
P. t.
(
1997
)
Identification of Smad7, a TGF-inducible antagonist of TGF- signalling.
Nature
289
,
631
635
Padgett
R. W.
,
St. Johnston
R. D.
,
Gelbart
W. M.
(
1987
)
A transcript from a Drosophila pattern gene predicts a protein homologous to the transforming growth factor-family.
Nature
325
,
81
84
Padgett
R. W.
,
Das
P.
,
Krishna
S.
(
1998
)
TGFsignaling, Smads, and tumor suppressors.
BioEssays
20
,
382
390
Panganiban
G. E.
,
Reuter
R.
,
Scott
M. P.
,
Hoffmann
F. M.
(
1990
)
A Drosophila growth factor homolog, decapentaplegic, regulates homeoticgene expression within and across germ layers during midgut morphogenesis.
Development
110
,
1041
1050
Patterson
G. I.
,
Koweek
A.
,
Wong
A.
,
Liu
Y.
,
Ruvkun
G.
(
1997
)
The DAF-3 Smad protein antagonizes TGF--related receptor signaling in the Caenorhabditis elegans dauer pathway.
Genes Dev
11
,
2679
2690
Ren
P.
,
Lim
C. S.
,
Johnsen
R.
,
Albert
P. S.
,
Pilgrim
D.
,
Riddle
D. L.
(
1996
)
Control of C. elegans larval development by neuronal expression of a TGF-homolog.
Science
274
,
1389
1391
Riddle
D. L.
,
Swanson
M. M.
,
Albert
P. S.
(
1981
)
Interacting genes in nematode dauer larva formation.
Nature
290
,
668
671
Savage
C.
,
Das
P.
,
Finelli
A. L.
,
Townsend
S. R.
,
Sun
C. Y.
,
Baird
S. E.
,
Padgett
R. W.
(
1996
)
Caenorhabditis elegans genes sma-2, sma-3, and sma-4 define a conserved family of transforming growth factorpathway components.
Proc. Natl. Acad. Sci. USA
93
,
790
794
Sekelsky
J. J.
,
Newfeld
S. J.
,
Raftery
L. A.
,
Chartoff
E. H.
,
Gelbart
W. M.
(
1995
)
Genetic characterization and cloning of Mothers against dpp, a gene required for decapentaplegic function in Drosophila melanogaster.
Genetics
139
,
1347
1358
Shimell
M. J.
,
Ferguson
E. L.
,
Childs
S. R.
,
O'Connor
M. B.
(
1991
)
The Drosophila dorsal-ventral patterning gene tolloid is related to human bone morphogenetic protein 1.
Cell
67
,
469
481
Suzuki
Y.
,
Yandell
M. D.
,
Roy
P. J.
,
Krishna
S.
,
Savage-Dunn
C.
,
Ross
R. M.
,
Padgett
R. W.
,
Wood
W. B.
(
1999
)
A BMP homolog acts as a dose-dependent regulator of body size and male tail patterning in Caenorhabditis elegans.
Development
126
,
241
250
Szuts
D.
,
Eresh
S.
,
Bienz
M.
(
1998
)
Functional intertwining of Dpp and EGFR signaling during Drosophila endoderm induction.
Genes Dev
12
,
2022
2035
Tsuneizumi
K.
,
Nakayama
T.
,
Kamoshida
Y.
,
Kornberg
T.
,
Christian
J.
,
Tabata
T.
(
1997
)
Daughters against dpp modulates organizing activity in Drosophila wing development.
Nature
389
,
627
631
Ventura
F.
,
Doody
J.
,
Liu
F.
,
Wrana
J. L.
,
Massague
J.
(
1994
)
Reconstitution and transphosphorylation of TGF-receptor complexes.
EMBO J
13
,
5581
5589
Weis-Garcia
F.
,
Massague
J.
(
1996
)
Complementation between kinase-defective and activation-defective TGF-receptors reveals a novel form of receptor cooperativity essential for signaling.
EMBO J
15
,
276
289
Wieser
R.
,
Wrana
J. L.
,
Massague
J.
(
1995
)
GS domain mutations that constitutively activate TR-I, the downstream signaling component in the TGF- receptor complex.
EMBO J
14
,
2199
2208
Wittmann
C.
,
Bossinger
O.
,
Goldstein
B.
,
Fleischmann
M.
,
Kohler
R.
,
Brunschwig
K.
,
Tobler
H.
,
Muller
F.
(
1997
)
The expression of the C. eleganslabial -like Hox gene ceh-13 during early embryogenesis relies on cell fate and on anteroposterior cell polarity.
Development
124
,
4193
4200
Wozney
J. M.
,
Rosen
V.
,
Celeste
A. J.
,
Mitsock
L. M.
,
Whitters
M. J.
(
1988
)
Novel regulators of bone formation: molecular clones and activities.
Science
242
,
1528
1531
Wrana
J. L.
,
Attisano
L.
,
Wieser
R.
,
Ventura
F.
,
Massague
J.
(
1994
)
Mechanism of activation of the TGF-receptor.
Nature
370
,
341
347
Wu
R. Y.
,
Zhang
Y.
,
Feng
X. H.
,
Derynck
R.
(
1997
)
Heteromeric and homomeric interactions correlate with signaling activity and functional cooperativity of Smad3 and Smad4/DPC4.
Mol. Cell Biol
17
,
2521
2528
Xie
T.
,
Finelli
A. L.
,
Padgett
R. W.
(
1994
)
The Drosophila saxophone gene: A serine-threonine kinase receptor of the TGF-superfamily.
Science
263
,
1756
1759
Yamashita
H.
,
ten Dijke
P.
,
Franzen
P.
,
Miyazono
K.
,
Heldin
C. H.
(
1994
)
Formation of hetero-oligomeric complexes of type I and type II receptors for transforming growth factor-beta.
J. Biol. Chem
269
,
20172
20178
Zhang
Y.
,
Feng
X.
,
We
R.
,
Derynck
R.
(
1996
)
Receptor-associated Mad homologues synergize as effectors of the TGF-response.
Nature
383
,
168
172
Zou
H.
,
Wieser
R.
,
Massague
J.
,
Niswander
L.
(
1997
)
Distinct roles of type I bone morphogenetic protein receptors in the formation and differentiation of cartilage.
Genes Dev
11
,
2191
2203
This content is only available via PDF.