Extracellular factors such as FGF and EGF control various aspects of morphogenesis, patterning and cellular proliferation in both invertebrates and vertebrates. In most systems, it is primarily the distribution of these factors that controls the differential behavior of the responding cells. Here we describe the role of Sprouty in eye development. Sprouty is an extracellular protein that has been shown to antagonize FGF signaling during tracheal branching in Drosophila. It is a novel type of protein with a highly conserved cysteine-rich region. In addition to the embryonic tracheal system, sprouty is also expressed in other tissues including the developing eye imaginal disc, embryonic chordotonal organ precursors and the midline glia. In each of these tissues, EGF receptor signaling is known to participate in the control of the correct number of neurons or glia. We show that, in all three tissues, the loss of sprouty results in supernumerary neurons or glia, respectively. Furthermore, overexpression of sprouty in wing veins and ovarian follicle cells, two other tissues where EGF signaling is required for patterning, results in phenotypes that resemble the loss-of-function phenotypes of Egf receptor. These results suggest that Sprouty acts as an antagonist of EGF as well as FGF signaling pathways. These receptor tyrosine kinase-mediated pathways may share not only intracellular signaling components but also extracellular factors that modulate the strength of the signal.

Allard
J. D.
,
Chang
H. C.
,
Herbst
R.
,
McNeill
H.
,
Simon
M. A.
(
1996
)
The SH2-containing tyrosine phosphatase corkscrew is required during signaling by sevenless, Ras1 and Raf.
Development
122
,
1137
1146
Basler
K.
,
Christen
B.
,
Hafen
E.
(
1991
)
Ligand-independent activation of the sevenless receptor tyrosine kinase changes the fate of cells in the developing Drosophila eye.
Cell
64
,
1069
1081
Beiman
M.
,
Shilo
B. Z.
,
Volk
T.
(
1996
)
Heartless, a Drosophila FGF receptor homolog, is essential for cell migration and establishment of several mesodermal lineages.
Genes Dev
10
,
2993
3002
Brunner
D.
,
Ducker
K.
,
Oellers
N.
,
Hafen
E.
,
Scholz
H.
,
Klämbt
C.
(
1994
)
The ETS domain protein pointed-P2 is a target of MAP kinase in the sevenless signal transduction pathway.
Nature
370
,
386
389
Carthew
R. W.
,
Rubin
G. M.
(
1990
)
seven in absentia, a gene required for specification of R7 cell fate in the Drosophila eye.
Cell
63
,
561
577
Clifford
R. J.
,
Schupbach
T.
(
1989
)
Coordinately and differentially mutable activities of torpedo, the Drosophila melanogaster homolog of the vertebrate EGF receptor gene.
Genetics
123
,
771
787
Dickson
B.
(
1995
)
Nuclear factors in sevenless signalling.
Trends Genet
11
,
106
111
Dickson
B.
,
Sprenger
F.
,
Morrison
D.
,
Hafen
E.
(
1992
)
Raf functions downstream of Ras1 in the Sevenless signal transduction pathway.
Nature
360
,
600
603
Dong
R.
,
Jacobs
J. R.
(
1997
)
Origin and differentiation of supernumerary midline glia in Drosophila embryos deficient for apoptosis.
Dev. Biol
190
,
165
177
Fortini
M. E.
,
Simon
M. A.
,
Rubin
G. M.
(
1992
)
Signalling by the sevenless protein tyrosine kinase is mimicked by Ras1 activation.
Nature
355
,
559
561
Freeman
M.
(
1997
)
Cell determination strategies in the Drosophila eye.
Development
124
,
261
270
Freeman
M.
(
1996
)
Reiterative use of the EGF receptor triggers differentiation of all cell types in the Drosophila eye.
Cell
87
,
651
660
Freeman
M.
(
1994
)
The spitz gene is required for photoreceptor determination in the Drosophila eye where it interacts with the EGF receptor.
Mech. Dev
48
,
25
33
Freeman
M.
,
Kimmel
B. E.
,
Rubin
G. M.
(
1992
)
Identifying targets of the rough homeobox gene of Drosophila: evidence that rhomboid functions in eye development.
Development
116
,
335
346
Freeman
M.
,
Klämbt
C.
,
Goodman
C. S.
,
Rubin
G. M.
(
1992
)
The argos gene encodes a diffusible factor that regulates cell fate decisions in the Drosophila eye.
Cell
69
,
963
975
Fujita
S. C.
,
Zipursky
S. L.
,
Benzer
S.
,
Ferrus
A.
,
Shotwell
S. L.
(
1982
)
Monoclonal antibodies against the Drosophila nervous system.
Proc. Natl. Acad. Sci. USA
79
Gaul
U.
,
Mardon
G.
,
Rubin
G. M.
(
1992
).
A putative Ras GTPase activating protein acts as a negative regulator of signaling by the Sevenless receptor tyrosine kinase.
Cell
68
,
1007
1019
Gisselbrecht
S.
,
Skeath
J. B.
,
Doe
C. Q.
,
Michelson
A. M.
(
1996
)
heartless encodes a fibroblast growth factor receptor (DFR1/DFGF-R2) involved in the directional migration of early mesodermal cells in the Drosophila embryo.
Genes Dev
10
,
3003
3017
Glazer
L.
,
Shilo
B. Z.
(
1991
)
The Drosophila FGF-R homolog is expressed in the embryonic tracheal system and appears to be required for directed tracheal cell extension.
Genes Dev
5
,
697
705
Golembo
M.
,
Schweitzer
R.
,
Freeman
M.
,
Shilo
B. Z.
(
1996
)
argos transcription is induced by the Drosophila EGF receptor pathway to form an inhibitory feedback loop.
Development
122
,
223
230
Gonzalez-Reyes
A.
,
Elliott
H.
,
St Johnston
D.
(
1995
)
Polarization of both major body axes in Drosophila by gurken-torpedo signalling.
Nature
375
,
654
658
Hacohen
N.
,
Kramer
S.
,
Sutherland
D.
,
Hiromi
Y.
,
Krasnow
M. A.
(
1998
)
sprouty encodes a novel antagonist of FGF signaling that patterns apical branching of the Drosophila airways.
Cell
92
,
253
263
Higashijima
S.
,
Kojima
T.
,
Michiue
T.
,
Ishimaru
S.
,
Emori
Y.
,
Saigo
K.
(
1992
)
Dual Bar homeo box genes of Drosophila required in two photoreceptor cells, R1 and R6, and primary pigment cells for normal eye development.
Genes Dev
6
,
50
60
Klämbt
C.
(
1993
)
The Drosophila gene pointed encodes two ETS-like proteins which are involved in the development of the midline glial cells.
Development
117
,
163
176
Klämbt
C.
,
Glazer
L.
,
Shilo
B. Z.
(
1992
)
breathless, a Drosophila FGF receptor homolog, is essential for migration of tracheal and specific midline glial cells.
Genes Dev
6
,
1668
1678
Klämbt
C.
,
Jacobs
J. R.
,
Goodman
C. S.
(
1991
)
The midline of the Drosophila central nervous system: a model for the genetic analysis of cell fate, cell migration, and growth cone guidance.
Cell
64
,
801
815
Kramer
S.
,
West
S. R.
,
Hiromi
Y.
(
1995
)
Cell fate control in the Drosophila retina by the orphan receptor seven-up: its role in the decisions mediated by the ras signaling pathway.
Development
121
,
1361
1372
Kretzschmar
D.
,
Brunner
A.
,
Wiersdorff
V.
,
Pflugfelder
G. O.
,
Heisenberg
M.
,
Schneuwly
S.
(
1992
)
Giant lens, a gene involved in cell determination and axon guidance in the visual system of Drosophila melanogaster.
EMBO J
11
,
2531
2539
Kulkarni
S. J.
,
Newby
L. M.
,
Jackson
F. R.
(
1994
)
Drosophila GABAergic systems. II. Mutational analysis of chromosomal segment 64AB, a region containing the glutamic acid decarboxylase gene.
Mol. Gen. Genet
243
,
555
564
Kumar
J. P.
,
Tio
M.
,
Hsiung
F.
,
Akopyan
S.
,
Gabay
L.
,
Seger
R.
,
Shilo
B. Z.
,
Moses
K.
(
1998
)
Dissecting the role ot the Drosophila EGF receptor in eye development and MAP kinase activation.
Development
125
,
3875
3885
Lage
P.
,
Jan
Y. N.
,
Jarman
A. P.
(
1997
)
Requirement for EGF receptor signalling in neural recruitment during formation of Drosophila chordotonal sense organ clusters.
Curr. Biol
7
,
166
175
Lai
Z. C.
,
Rubin
G. M.
(
1992
)
Negative control of photoreceptor development in Drosophila by the product of the yan gene, an ETS domain protein.
Cell
70
,
609
620
Lawrence
P. A.
,
Green
S. M.
(
1979
)
Cell lineage in the developing retina of Drosophila.
Dev. Biol
71
,
142
152
Lin
D. M.
,
Goodman
C. S.
(
1994
)
Ectopic and increased expression of Fasciclin II alters motoneuron growth cone guidance.
Neuron
13
,
507
523
Livneh
E.
,
Glazer
L.
,
Segal
D.
,
Schlessinger
J.
,
Shilo
B. Z.
(
1985
)
The Drosophila EGF receptor gene homolog: conservation of both hormone binding and kinase domains.
Cell
40
,
599
607
Mlodzik
M.
,
Hiromi
Y.
,
Goodman
C. S.
,
Rubin
G. M.
(
1992
)
The presumptive R7 cell of the developing Drosophila eye receives positional information independent of sevenless, boss and sina.
Mech. Dev
37
,
37
42
Mlodzik
M.
,
Hiromi
Y.
,
Weber
U.
,
Goodman
C. S.
,
Rubin
G. M.
(
1990
)
The Drosophila seven-up gene, a member of the steroid receptor gene superfamily, controls photoreceptor cell fates.
Cell
60
,
211
224
Neuman-Silberberg
F. S.
,
Schupbach
T.
(
1993
)
The Drosophila dorsoventral patterning gene gurken produces a dorsally localized RNA and encodes a TGF alpha-like protein.
Cell
75
,
165
174
O'Neill
E. M.
,
Rebay
I.
,
Tjian
R.
,
Rubin
G. M.
(
1994
)
The activities of two Ets-related transcription factors required for Drosophila eye development are modulated by the Ras/MAPK pathway.
Cell
78
,
137
147
O'Neill
J. W.
,
Bier
E.
(
1994
)
Double-label in situ hybridization using biotin and digoxigenin-tagged RNA probes.
Biotechniques
17
,
870
–.
Okabe
M.
,
Okano
H.
(
1997
)
Two-step induction of chordotonal organ precursors in Drosophila embryogenesis.
Development
124
,
1045
1053
Okabe
M.
,
Sawamoto
K.
,
Okano
H.
(
1996
)
The function of the Drosophila argos gene product in the development of embryonic chordotonal organs.
Dev. Biol
175
,
37
49
Okano
H.
,
Hayashi
S.
,
Tanimura
T.
,
Sawamoto
K.
,
Yoshikawa
S.
,
Watanabe
J.
,
Iwasaki
M.
,
Hirose
S.
,
Mikoshiba
K.
,
Montell
C.
(
1992
)
Regulation of Drosophila neural development by a putative secreted protein.
Differentiation
52
,
1
11
Peifer
M.
,
Wieschaus
E.
(
1990
)
The segment polarity gene armadillo encodes a functionally modular protein that is the Drosophila homolog of human plakoglobin.
Cell
63
,
1167
1176
Perrimon
N.
,
Perkins
L. A.
(
1997
)
There must be 50 ways to rule the signal: the case of the Drosophila EGF receptor.
Cell
89
,
13
16
Queenan
A. M.
,
Ghabrial
A.
,
Schupbach
T.
(
1997
)
Ectopic activation of torpedo/Egfr, a Drosophila receptor tyrosine kinase, dorsalizes both the eggshell and the embryo.
Development
124
,
3871
3880
Ready
D. F.
,
Hanson
T. E.
,
Benzer
S.
(
1976
)
Development of the Drosophila retina, a neurocrystalline lattice.
Dev. Biol
53
,
217
240
Roth
S.
,
Neuman-Silberberg
F. S.
,
Barcelo
G.
,
Schupbach
T.
(
1995
)
cornichon and the EGF receptor signaling process are necessary for both anterior-posterior and dorsal-ventral pattern formation in Drosophila.
Cell
81
,
967
978
Rutledge
B. J.
,
Zhang
K.
,
Bier
E.
,
Jan
Y. N.
,
Perrimon
N.
(
1992
)
The Drosophila spitz gene encodes a putative EGF-like growth factor involved in dorsal-ventral axis formation and neurogenesis.
Genes Dev
6
,
1503
1517
Schlessinger
J.
(
1993
)
How receptor tyrosine kinases activate Ras.
Trends Biochem. Sci
18
,
273
275
Schnepp
B.
,
Grumbling
G.
,
Donaldson
T.
,
Simcox
A.
(
1996
)
Vein is a novel component in the Drosophila epidermal growth factor receptorpathway with similarity to the neuregulins.
Genes Dev
10
,
2302
2313
Scholz
H.
,
Sadlowski
E.
,
Klaes
A.
,
Klämbt
C.
(
1997
)
Control of midline glia development in the embryonic Drosophila CNS.
Mech. Dev
64
,
137
151
Schupbach
T.
(
1987
)
Germ line and soma cooperate during oogenesis to establish the dorsoventral pattern of egg shell and embryo in Drosophila melanogaster.
Cell
49
,
699
707
Schupbach
T.
,
Wieschaus
E.
(
1998
)
Probing patterns of gene expression in Drosophila epithelial development.
Int. J. Dev. Biol.
42
Schweitzer
R.
,
Howes
R.
,
Smith
R.
,
Shilo
B. Z.
,
Freeman
M.
(
1995
).
Inhibition of Drosophila EGF receptor activation by the secreted protein Argos.
Nature
376
,
699
702
Schweitzer
R.
,
Shilo
B. Z.
(
1997
)
A thousand and one roles for the Drosophila EGF receptor.
Trends Genet
13
,
191
196
Shishido
E.
,
Ono
N.
,
Kojima
T.
,
Saigo
K.
(
1997
)
Requirements of DFR1/Heartless, a mesoderm-specific Drosophila FGF-receptor, for the formation of heart, visceral and somatic muscles, and ensheathing of longitudinal axon tracts in CNS.
Development
124
,
2119
2128
Simcox
A. A.
,
Grumbling
G.
,
Schnepp
B.
,
Bennington-Mathias
C.
,
Hersperger
E.
,
Shearn
A.
(
1996
)
Molecular, phenotypic, and expression analysis of vein, a gene required for growth of the Drosophila wing disc.
Dev. Biol
177
,
475
489
Sonnenfeld
M. J.
,
Jacobs
J. R.
(
1995
)
Apoptosis of the midline glia during Drosphila embryogenesis: a correlation with axon contact.
Development
121
,
569
578
Sturtevant
M. A.
,
O'Neill
J. W.
,
Bier
E.
(
1994
)
Down-regulation of Drosophila Egf-r mRNA levels following hyperactivated receptor signaling.
Development
120
,
2593
2600
Sutherland
D.
,
Samakovlis
C.
,
Krasnow
M. A.
(
1996
)
branchless encodes a Drosophila FGF homolog that controls tracheal cell migration and the pattern of branching.
Cell
87
,
1091
1101
Tio
M.
,
Ma
C.
,
Moses
K.
(
1994
)
spitz, a Drosophila homolog of transforming growth factor-alpha, is required in the founding photoreceptor cells of the compound eye facets.
Mech. Dev
48
,
13
23
Tomlinson
A.
,
Ready
D. F.
(
1987
)
Neuronal differentiation in the Drosophila ommatidium.
Dev. Biol
120
,
366
376
Tomlinson
A.
,
Ready
D. F.
(
1986
)
sevenless: a cell specific homeotic mutation of the Drosophila eye.
Science
231
,
400
402
Van Vactor
D. L.
Jr.
,
Cagan
R. L.
,
Krämer
H.
,
Zipursky
S. L.
(
1991
)
Induction in the developing compound eye of Drosophila: multiple mechanisms restrict R7 induction to a single retinal precursor cell.
Cell
67
,
1145
1155
Wohlwill
A. D.
,
Bonner
J. J.
(
1991
)
Genetic analysis of chromosome region 63 of Drosophila melanogaster.
Genetics
128
,
763
775
Wolff
T.
,
Ready
D. F.
(
1991
)
The beginning of pattern formation in the Drosophila compound eye: the morphogenetic furrow and the second mitotic wave.
Development
113
,
841
850
Wolff
T.
,
Ready
D. F.
(
1991
)
Cell death in normal and rough eye mutants of Drosophila.
Development
113
,
825
839
Xu
T.
,
Rubin
G. M.
(
1993
)
Analysis of genetic mosaics in developing and adult Drosophila tissues.
Development
117
,
1223
1237
Zipursky
S. L.
,
Rubin
G. M.
(
1994
)
Determination of neuronal cell fate: lessons from the R7 neuron of Drosophila.
Ann. Rev. Neurosci
17
,
373
397
Casci
T.
,
Vinos
J.
,
Freeman
M.
(
1999
)
Sprouty, an intracellular inhibitor of Ras signaling.
Cell
96
,
655
665
This content is only available via PDF.