Photoreceptor and cone cells in the Drosophila eye are recruited following activation of the epidermal growth factor receptor (EGFR) pathway. We have identified echinoid (ed) as a novel putative cell adhesion molecule that negatively regulates EGFR signaling. The ed mutant phenotype is associated with extra photoreceptor and cone cells. Conversely, ectopic expression of ed in the eye leads to a reduction in the number of photoreceptor cells. ed expression is independent of EGFR signaling and ED is localized to the plasma membrane of every cells throughout the eye disc. We present evidence that ed acts nonautonomously to generate extra R7 cells by a mechanism that is sina-independent but upstream of Tramtrack (TTK88). Together, our results support a model whereby ED defines an independent pathway that antagonizes EGFR signaling by regulating the activity, but not the level, of the TTK88 transcriptional repressor.
Reference
Baker
N. E.
, Rubin
G. M.
(1989
) Effect on eye development of dominant mutations in Drosophila homologue of the EGF receptor.
Nature
340
, 150
–153
Bang
A. G.
, Kintner
C.
(2000
) Rhomboid and Star facilitate presentation and processing of the Drosophila TGF-homolog Spitz.
Genes Dev
14
, 177
–186
Brand
A. H.
, Perrimon
N.
(1993
) Targeted gene expression as a means of altering cell fates and generating dominant phenotypes.
Development
118
, 401
–415
Brunner
D.
, Oellers
N.
, Szabad
J.
, Biggs
W. H.
, Zipursky
S. L.
, Hafen
E.
(1994
) A gain of function mutation in Drosophila MAP kinase activates multiple receptor kinase signaling pathways.
Cell
76
, 875
–888
Brunner
D.
, Ducker
K.
, Oellers
N.
, Hafen
E.
, Scholz
H.
, Klambt
C.
(1994
) The ETS domain protein Pointed-P2 is a target of MAP kinase in the Sevenless signal transduction pathway.
Nature
370
, 386
–389
Capdevila
J.
, Guerrero
I.
(1994
) Targeted expression of the signaling molecule decapentaplegic induces pattern duplications and growth alterations in Drosophila wings.
EMBO J
13
, 4459
–4468
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
Casci
T.
, Vinos
J.
, Freeman
M.
(1999
) Sprouty, an intracellular inhibitor of Ras signaling.
Cell
96
, 655
–665
Cavener
D. R.
(1987
) Comparison of the consensus sequence flanking translational start sites in Drosophila and vertebrates.
Nucleic Acids Res
15
, 1353
–1361
Chou
T. B.
, Noll
E.
, Perrimon
N.
(1993
) Autosomal P[ovoD1] dominant female-sterile insertions in Drosophila and their use in generating germ-line chimeras.
Development
119
, 1359
–1369
de Belle
J. S.
, Sokolowski
M. B.
, Hilliker
A. J.
(1993
) Genetic analysis of foraging microregion of Drosophila melanogaster.
Genome
36
, 94
–101
Dickson
B.
, Sprenger
F.
, Morrison
D.
, Hafen
E.
(1992
) Raf functions downstream of Ras1 in the sevenless signal transduction pathway.
Nature
360
, 600
–603
Dominguez
M.
, Wasserman
J. D.
, Freeman
M.
(1998
) Multiple functions of the EGF receptor in Drosophila eye development.
Curr. Biol
8
, 1039
–1048
Dong
X.
, Tsuda
L.
, Zavitz
K. H.
, Lin
M.
, Li
S.
, Carthew
R. W.
, Zipursky
S. L.
(1999
) ebi regulates epidermal growth factor receptor signaling pathways in Drosophila.
Genes Dev
13
, 954
–965
Dubreuil
R. R.
, MacVicar
G.
, Dissanayake
S.
, Liu
C.
, Homer
D.
, Hortsch
M.
(1996
) Neuroglian-mediated cell adhesion induces assembly of the membrane skeleton at cell contact sites.
J. Cell Biol
133
, 647
–655
Fortini
M. E.
, Simon
M. A.
, Rubin
G. M.
(1992
) Signaling by the sevenless protein tyrosine kinase is mimicked by Ras1 activation.
Nature
355
, 559
–561
Freeman
M.
, Klambt
C.
, Goodman
C. S.
, Rubin
G. M.
(1992
) The argos gene encodes a diffusible factor that regulate cell fate decisions in the Drosophila eye.
Cell
69
, 963
–975
Freeman
M.
(1994
) Misexpression of the Drosophila argos gene, a secreted regulator of cell determination.
Development
120
, 2297
–2304
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.
(1997
) Cell determination strategies in the Drosophila eye.
Development
124
, 261
–270
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
Ghiglione
C.
, Carraway
K. L.
III, Amundadottir
L. T.
, Boswell
R. E.
, Perrimon
N.
, Duffy
J. B.
(1999
) The transmembrane molecule kekkon1 acts in a feedback loop to negatively regulate the activity of the Drosophila EGF receptor during oogenesis.
Cell
96
, 847
–856
Herbst
R.
, Carroll
P. M.
, Allard
J. D.
, Schilling
J.
, Raabe
T.
, Simon
M. A.
(1996
) Daughter of sevenless is a substrate of the phosphotyrosine phosphatase corkscrew and functions during sevenless signaling.
Cell
85
, 899
–909
Hortsch
M.
(1996
) The L1 family of neuronal cell adhesion molecules: old proteins performing new tricks.
Neuron
17
, 587
–593
Hortsch
M.
, Homer
D.
, Malhotra
J. D.
, Chang
S.
, Frankel
J.
, Jefford
G.
, Dubreuil
R. R.
(1998
) Structural requirements for outside-in and inside-out signaling by Drosophila Neuroglian, a member of the L1 family of cell adhesion molecules.
J. Cell Biol
142
, 251
–261
Hou
X. S.
, Chou
T.-B.
, Melnick
M. B.
, Perrimon
N.
(1995
) The torsoreceptor tyrosine kinase can activate raf in a Ras-independent pathway.
Cell
81
, 63
–71
Hynes
R. O.
(1986
) Molecular biology of fibronectin.
Annu. Rev. Cell Biol
1
, 67
–90
Jin
M. H.
, Sawamoto
K.
, Ito
M.
, Okano
H.
(2000
) The interaction between the Drosophila secreted protein argos and the epidermal growth factor receptor inhibits dimerization of the receptor and binding of secreted spitz to the receptor.
Mol. Cell. Biol
20
, 2098
–2107
Karim
F. D.
, Chang
H. C.
, Therrien
M.
, Wassarman
D. A.
, Laverty
T.
, Rubin
G. M.
(1996
) A screen for genes that function downstream of Ras1 during Drosophila eye development.
Genetics
143
, 315
–329
Karim
F. D.
, Rubin
G. M.
(1999
) PTP-ER, a novel tyrosine phosphatase, functions downstream of Ras1 to downregulate MAPK kinase during Drosophila eye development.
Cell
3
, 741
–750
Kimmel
B. E.
, Heberlein
U.
, Rubin
G. M.
(1990
) The homeodomain protein Rough is expressed in a subset of cells in the developing Drosophila eye where it can specify photoreceptor cell subtype.
Genes Dev
4
, 712
–727
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
Lai
Z.-C.
, Harrison
S. D.
, Karim
F.
, Li
Y.
, Rubin
G. M.
(1996
) Loss of tramtrack gene activity results in ectopic R7 cell formation, even in a sina mutant background.
Proc. Natl. Acad. Sci. USA
93
, 5025
–5030
Li
S.
, Li
Y.
, Carthew
R. W.
, Lai
Z.-C.
(1997
) Photoreceptor cell differentiation requires regulated proteolysis of the transcriptional repressor Tramtrack.
Cell
90
, 469
–478
Miyamoto
S.
, Teramoto
H.
, Gutkind
J. S.
, Yamada
K. M.
(1996
) Integrins can collaborate with growth factors for phosphorylation of receptor tyrosine kinases and MAP kinase activation: roles of integrin aggregation and occupancy of receptors.
J. Cell Biol
135
, 1633
–1642
Moghal
N.
, Neel
B. G.
(1998
) Integration of growth factor, extracellular matrix, and retinoid signals during bronchial epithelial cell differentiation.
Mol. Cell. Biol
18
, 6666
–6678
Moghal
N.
, Sternberg
P. W.
(1999
) Multiple positive and negative regulators of signaling by the EGF-receptor.
Curr. Opin. Cell Biol
11
, 190
–196
Moro
L.
, Venturino
M.
, Bozzo
C.
, Silengo
L.
, Altruda
F.
, Beguinot
L.
, Tarone
G.
, Defilippi
P.
(1998
) Integrins induce activation of EGF receptor: role in MAP kinase induction and adhesion-dependent cell survival.
EMBO J
17
, 6622
–6632
Newsome
T. P.
, Asling
B.
, Dickson
B. J.
(2000
) Analysis of Drosophila photoreceptor axon guidance in eye-specific mosaics.
Development
127
, 851
–860
O'Neill
E. M.
, Rebay
I.
, Tijian
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
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
Raabe
T.
, Riesgo-Escovar
J.
, Liu
X.
, Bausenwein
B. S.
, Deak
P.
, Maroy
P.
, Hafen
E.
(1996
) Dos, a novel pleckstrin homology domain-containing protein required for signal transduction between sevenless and Ras1 in Drosophila.
Cell
85
, 911
–920
Read
D.
, Manley
J. L.
(1992
) Alternatively spliced transcripts of the Drosophila tramtrack gene encode zinc finger proteins with distinct DNA binding specifications.
EMBO J
11
, 1035
–1044
Rebay
I.
, Rubin
G. M.
(1995
) Yan functions as a general inhibitor of differentiation and is negatively regulated by activation of the Ras1/MAPK pathway.
Cell
81
, 857
–866
Reichman-Fried
M.
, Dickson
B.
, Hafen
E.
, Shilo
B.-Z.
(1994
) Elucidation of the role of breathless, a Drosophila FGF receptor homolog, in tracheal cell migration.
Genes Dev
8
, 428
–439
Schweitzer
R.
, Howes
R.
, Smith
R.
, Shilo
B.-Z.
, Freeman
M.
(1995
) Inhibition of Drosophila EGF receptor activated 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
Simon
M. A.
, Bowtell
D. D.
, Dodson
G. S.
, Laverty
T. R.
, Rubin
G. M.
(1991
) Ras1 and a putative guanine nucleotide exchange factor perform crucial steps in signaling by the sevenless protein tyrosine kinase.
Cell
67
, 701
–716
Spradling
A. C.
, Rubin
G. M.
(1982
) Transposition of cloned P elements into Drosophila germ line chromosome.
Science
218
, 341
–347
Tan
P. B. O.
, Kim
S. K.
(1999
) Signaling specificity.
Trends Genet
15
, 145
–149
Tang
A. H.
, Neufeld
T. P.
, Kwan
E.
, Rubin
G. M.
(1997
) PHYL acts to down-regulate TTK88, a transcriptional repressor of neuronal cell fates, by a SINA-dependent mechanism.
Cell
90
, 459
–467
Torok
T.
, Tick
G.
, Alvarado
M.
, Kiss
I.
(1993
) P-lacW insertional mutagenesis on the second chromosome of Drosophila melanogaster: isolation of lethals with different overgrowth phenotypes.
Genetics
135
, 71
–80
Williams
A. F.
, Barclay
A. N.
(1988
) The immunoglobulin superfamily-domains for cell surface recognition.
Annu. Rev. Immunol
6
, 381
–405
Wolff
T.
, Ready
D. F.
(1991
) Cell death in normal and rougheye mutants of Drosophila.
Development
113
, 825
–839
Xiong
W. C.
, Montell
C.
(1993
) Tramtrack is a transcriptional repressor required for cell fate determination in the Drosophila eye.
Genes Dev
7
, 1085
–1096
Xu
T.
, Rubin
G. M.
(1993
) Analysis of genetic mosaics in developing and adult Drosophila tissues.
Development
117
, 1223
–1237
Yamauchi
T.
, Ueki
K.
, Tobe
K.
, Tamemoto
H.
, Sekine
N.
, Wada
M.
, Honjo
M.
, Takahashi
M.
, Takahashi
T.
, Hirai
H.
, et al. (1997
) Tyrosine phosphorylation of the EGF receptor by the kinase Jak2 is induced by growth hormone.
Nature
390
, 91
–96
Zak
N. B.
, Shilo
B.-Z.
(1992
) Localization of DER and the pattern of cell division in wild-type and Ellipse eye imaginal discs.
Dev. Biol
149
, 448
–456
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