Growth factors are believed to play an important role in regulating cell fate and cell behavior during embryonic development. Transforming growth factor alpha (TGF alpha), a member of the epidermal growth factor (EGF) superfamily, is a small polypeptide growth factor. Upon binding to its receptor, the EGF receptor (EGFR), TGF alpha can exert diverse biological activities, such as induction of cell proliferation or differentiation. To explore the possibility that TGF alpha might regulate cell fate during murine eye development, we generated transgenic mice that express human TGF alpha in the lens under the control of the mouse alpha A-crystallin promoter. The transgenic mice displayed multiple eye defects, including corneal opacities, cataracts and microphthalmia. At early embryonic stages TGF alpha induced the perioptic mesenchymal cells to migrate abnormally into the eye and accumulate around the lens. In situ hybridization revealed that the EGFR mRNA is highly expressed in the perioptic mesenchyme, suggesting that the migratory response is mediated by receptor activation. In order to test this model, the TGF alpha transgenic mice were bred to EGFR mutant waved-2 (wa-2) mice. We found that the eye defects of the TGF alpha transgenic mice are significantly abated in the wa-2 homozygote background. Because the EGFR mutation in the wa-2 mice is located in the receptor kinase domain, this result indicates that the receptor tyrosine kinase activity is critical for signaling the migratory response. Taken together, our studies demonstrate that TGF alpha is capable of altering the migratory decisions and behavior of perioptic mesenchyme during eye development.

Adamson
E. D.
(
1990
)
Developmental activities of the epidermal growth factor receptor.
Curr. Top. Dev. Biol
24
,
1
29
Anchan
R. M.
,
Reh
T. A.
,
Angello
J.
,
Balliet
A.
,
Walker
M.
(
1991
)
EGF and TGF-stimulate retinal neuroepithelial cell proliferation in vitro.
Neuron
6
,
923
926
Anderson
D. M.
,
Lyman
S. D.
,
Baird
A.
,
Wignall
J. M.
,
Eisenman
J.
,
Rauch
C.
,
March
C. J.
,
Boswell
H. S.
,
Gimpel
S. D.
,
Cosman
D.
,
Williams
D. E.
(
1990
)
Molecular cloning of mast cell growth factor, a hematopoietin that is active in both membrane bound and soluble forms.
Cell
63
,
235
–.
Anklesaria
P.
,
Teixido
J.
,
Laiho
M.
,
Pierce
J. H.
,
Greenberger
J. S.
,
Massague
J.
(
1990
)
Cell-cell adhesion mediated by binding of membrane-anchored transformation growth factorto epidermal growth factor receptors promotes cell proliferation.
Proc. Natl. Acad. Sci. USA
87
,
3289
3293
Barrandon
Y.
,
Green
H.
(
1987
)
Cell migration is essential for the sustained growth of keratinocyte colonies: the roles of transforming growth factor-and epidermal growth factor.
Cell
50
,
1131
1137
Barton
C. M.
,
Hall
P. A.
,
Hughes
C. M.
,
Gullick
W. J.
,
Lemoine
N. R.
(
1991
)
Transforming growth factor alpha and epidermal growth factor in human pancreatic cancer.
J. Pathol
163
,
111
116
Blasband
A. J.
,
Gilligan
G. M.
,
Winchell
L. F.
,
Wong
S. T.
,
Luetteke
N. C.
,
Rogers
K. T.
,
Lee
D. C.
(
1990
)
Expression of the TGFintegral membrane precursor induces transformation of NRK cells.
Oncogene
5
,
1213
1221
Chabot
B.
,
Stephenson
D. A.
,
Chapman
V. M.
,
Besmer
P.
,
Bernstein
A.
(
1988
)
The proto-oncogene c-kit encoding a transmembrane tyrosine kinase receptor maps to the mouse W locus.
Nature
335
,
88
89
Cohen
S.
(
1962
)
Isolation of a mouse submaxillary gland protein accelerating incisor eruption and eyelid opening in the newborn animal.
J. Biol. Chem
237
,
1555
1562
Coulombre
J. L.
,
Coulombre
A. J.
(
1963
)
Lens development: Fibre elongation and lens orientation.
Science
142
,
1489
1490
Decsi
A.
,
Peiffer
R. L.
,
Qiu
T.
,
Lee
D. C.
,
Friday
J. T.
,
Bautch
V. L.
(
1994
)
Lens expression of TGFin transgenic mice produces two distinct eye pathologies in the absence of tumors.
Oncogene
9
,
1965
1975
Derynck
R.
,
Goeddel
D. V.
,
Ullrich
A.
,
Gutterman
J. U.
,
Williams
R. D.
,
Bringman
T. S.
,
Berger
W. H.
(
1987
)
Synthesis of messenger RNAs for transforming growth factorand and the epidermal growth factor receptor by human tumors.
Cancer Res
47
,
707
712
Fiers
W.
,
Contreras
R.
,
Haegeman
G.
,
Rogiers
R.
,
van der Voorde
A.
,
van Heuverswyn
H.
,
van Herreseghe
J.
,
Volckaert
G.
,
Ysebaert
M.
(
1978
)
The complete nucleotide sequence of SV40 DNA.
Nature
273
,
113
119
Flanagan
J. G.
,
Chan
D. C.
,
Leder
P.
(
1991
)
Transmembrane form of the kit ligand growth factor is determined by alternative splicing and is missing in the Sldmutant.
Cell
64
,
1025
1035
Flanagan
J. G.
,
Leder
P.
(
1990
)
The kit ligand: a cell surface molecule altered in steel mutant fibroblasts.
Cell
63
,
185
194
Geissler
E. N.
,
Ryan
M. A.
,
Housman
D. E.
(
1988
)
The dominant-white spotting (W) locus of the mouse encodes the c-kit proto-oncogene.
Cell
55
,
185
192
Gorman
C. M.
,
Moffat
L. F.
,
Howard
B. H.
(
1982
)
Recombinant genomes which express chloramphenicol acetyltransferase in mammalian cells.
Mol. Cell. Biol
2
,
1044
1055
Grant
M. B.
,
Khaw
P. T.
,
Schultz
G. S.
,
Adams
J. L.
,
Shimizu
R. W.
(
1992
)
Effects of epidermal growth factor, fibroblast growth factor, and transforming growth factor-on corneal cell chemotaxis.
Invest. Ophthalmol. Vis. Sci
33
,
3292
3301
Gurdon
J. B.
(
1992
)
The generation of diversity and pattern in animal development.
Cell
68
,
185
199
Higashiyama
S.
,
Abraham
J. A.
,
Miller
J.
,
Fiddes
J. C.
,
Klagsbrun
M.
(
1991
)
A heparin-binding growth factor secreted by macrophage-like cells that is related to EGF.
Science
251
,
936
939
Jessell
T. M.
,
Melton
D. A.
(
1992
)
Diffusible factors in vertebrate embryonic induction.
Cell
68
,
257
270
Jhappan
C.
,
Stahle
C.
,
Harkins
R. N.
,
Fausto
N.
,
Smith
G.
,
Merlino
G.
(
1990
)
TGFoverexpression in transgenic mice induces liver neoplasia and abnormal development of the mammary gland and pancreas.
Cell
61
,
1137
1146
Khaw
P. T.
,
Schultz
G. S.
,
MacKay
S. L. D.
,
Chegini
N.
,
Rotatori
D. S.
,
Adams
J. L.
,
Shimizu
R. W.
(
1992
)
Detection of transforming growth factor-messenger RNA and protein in human corneal epithelial cells.
Invest. Ophthalmol. Vis. Sci
33
,
3302
3306
Kimura
H.
,
Fischer
W. H.
,
Schubert
D.
(
1990
)
Structure, expression and function of a schwannoma-derived growth factor.
Nature
348
,
257
260
Kinashi
T.
,
Springer
T. A.
(
1994
)
Steel factor and c-kit regulate cell-matrix adhesion.
Blood
4
,
1033
1038
Lee
L. W.
,
Raymond
V. W.
,
Tsao
M.-S.
,
Lee
D. C.
,
Earp
H. S.
,
Grisham
J. W.
(
1991
)
Clonal cosegregation of tumorigenicity with overexpression of c-myc and transforming growth factorgenes in chemically transformed rat liver epithelial cells.
Cancer Res
51
,
5238
5344
Lillien
L.
,
Cepko
C.
(
1992
)
Control of proliferation in the retina: temporal changes in responsiveness to FGF and TGF.
Development
115
,
253
266
Luetteke
N. C.
,
Lee
D. C.
,
Palmiter
R. D.
,
Brinster
R. L.
,
Sandgren
E. P.
(
1993
)
Regulation of fat and muscle development by TGFin transgenic mice and cultured cells.
Cell Growth Differ
3
,
203
213
Luetteke
N. C.
,
Qiu
T. H.
,
Peiffer
R. L.
,
Oliver
P.
,
Smithies
O.
,
Lee
D. C.
(
1993
)
TGFdeficiency results in hair follicle and eye abnormalities in targeted and waved-1 mice.
Cell
73
,
263
278
Luetteke
N. C.
,
Phillips
H. K.
,
Qiu
T. H.
,
Copeland
N. G.
,
Earp
H. S.
,
Jenkins
N. A.
,
Lee
D. C.
(
1994
)
The mouse waved-2 phenotype results from a point mutation in the EGF receptor tyrosine kinase.
Genes & Dev
8
,
339
413
Mann
G. B.
,
Fowler
K. J.
,
Gabriel
A.
,
Nice
E. C.
,
Williams
L.
,
Dunn
A. R.
(
1993
)
Mice with a null mutation of the TGFgene have abnormal skin architecture, wavy hair, and curly whiskers and often develop corneal inflammation.
Cell
73
,
249
261
Massague
J.
(
1990
)
Transforming growth factor-: A model for membrane-anchored growth factors.
J. Biol. Chem
265
,
21393
21396
Massague
J.
,
Pandiella
A.
(
1993
)
Membrane-anchored growth factors.
Annu. Rev. Biochem
62
,
515
541
Matsui
Y.
,
Halter
S. A.
,
Holt
J. T.
,
Hogan
B. L. M.
,
Coffey
R. J.
(
1990
)
Development of mammary hyperplasia and neoplasia in MMTV-TGFtransgenic mice.
Cell
61
,
1147
1155
McAvoy
J. W.
,
Chamberlain
C. G.
(
1990
)
Growth factors in the eye.
Progress in Growth Factor Research
2
,
29
43
McGeady
M. L.
,
Kerby
S.
,
Shankar
V.
,
Ciardiello
F.
,
Salomon
D.
,
Seidman
M.
(
1989
)
Infection with a TGF-retroviral vector transforms normal mouse mammary epithelial cells but not normal rat fibroblasts.
Oncogene
4
,
1375
1382
Meininger
C. J.
,
Yano
H.
,
Rottapei
R.
,
Bernstein
A.
,
Zsebo
K. M.
,
Zetter
B. R.
(
1992
)
The c-kit receptor ligand functions as a mast cell chemoattactant.
Blood
4
,
958
963
Overbeek
P. A.
,
Chepelinsky
A. B.
,
Khillan
J. S.
,
Piatigorsky
J.
,
Westphal
H.
(
1985
)
Lens-specific expression and developmental regulation of the bacterial chloramphenicol acetyltransferase gene driven by the murine alpha A-crystallin promoter in transgenic mice.
Proc. Natl. Acad. Sci. USA
82
,
7815
7819
Partanen
A.-M.
(
1990
)
Epidermal growth factor and transforming growth factor-in the development of epithelial-mesenchymal organs of the mouse.
Curr. Top. Dev. Biol
24
,
31
55
Petch
L. A.
,
Harris
J.
,
Raymond
V. W.
,
Blasband
A.
,
Lee
D. C.
,
Earp
H. S.
(
1990
)
A truncated, secreted form of the epidermal growth factor receptor is encoded by an alternative spliced transcript in normal rat tissue.
Mol. Cell. Biol
10
,
2973
2982
Piatigorsky
J.
(
1981
)
Lens differentiation in vertebrates: A review of cellular and molecular features.
Differentiation
19
,
134
153
Rappole
D. A.
,
Brenner
C. A.
,
Schultz
R.
,
Mark
D.
,
Werb
Z.
(
1988
)
Developmental expression of PDGF, TGF-, and TGF- genes in preimplantation mouse embryos.
Science
241
,
1823
1825
Robinson
M. L.
,
Overbeek
P. A.
,
Verran
D. J.
,
Grizzle
W. E.
,
Stockard
C. R.
,
Friesel
R.
,
Maciag
T.
,
Thompson
J. A.
(
1995
)
Extracellular FGF-1 acts as a lens differentiation factor in transgenic mice.
Development
121
,
505
514
Rosenthal
A.
,
Lindquist
P. B.
,
Bringman
T. S.
,
Goeddel
D. V.
,
Derynck
R.
(
1986
)
Expression in rat fibroblasts of a human transforming growth factor-cDNA results in transformation.
Cell
46
,
301
309
Russell
E. S.
(
1979
)
Developmental studies of the mouse: a review for geneticists.
Adv. Genet
20
,
357
459
Sandgren
E. P.
,
Luetteke
N. C.
,
Palmiter
R. D.
,
Brinster
R. L.
,
Lee
D. C.
(
1990
)
Overexpression of TGFin transgenic mice: induction of epithelial hyperplasia, pancreatic metaplasia, and carcinoma of the breast.
Cell
61
,
1121
1135
Schreiber
A. B.
,
Winkler
M. E.
,
Derynck
R.
(
1986
)
Transforming growth factor-: a more potent angiogenic mediator than epidermal growth factor.
Science
232
,
1250
1253
Schultz
G. S.
,
White
M.
,
Mitchell
R.
,
Brown
G.
,
Lynch
J.
,
Twardzik
D. R.
,
Todaro
G. J.
(
1987
)
Epithelial wound healing enhanced by transforming growth factor-and vaccinia growth factor.
Science
235
,
350
352
Schultz
G. S.
,
Chegini
N.
,
Grant
M.
,
Khaw
P.
,
MacKay
S.
(
1992
)
Effects of growth factors on corneal wound healing.
Acta Ophthal
70
,
60
66
Shoyab
M.
,
Plowman
G. D.
,
McDonald
V. L.
,
Bradley
J. G.
,
Todaro
G. J.
(
1989
)
Structure and function of human amphiregulin: a member of the epidermal growth factor family.
Science
243
,
1074
76
Smith
J. M.
,
Sporn
M. B.
,
Roberts
A. B.
,
Derynck
R.
,
Winkler
M. E.
,
Gregory
H.
(
1985
)
Human transforming growth factor-causes precocious eyelid opening in newborn mice.
Nature
315
,
515
516
Snider
W. D.
(
1994
)
Functions of the neurotrophins during nervous system development: what the knockouts are teaching us.
Cell
77
,
627
638
Taketo
M.
,
Schroeder
A. C.
,
Mobraaten
L. E.
,
Gunning
K. B.
,
Hanten
G.
,
Fox
R. R.
,
Roderick
T. H.
,
Stewart
C. L.
,
Lilly
F.
,
Hansen
C. T.
,
Overbeek
P. A.
(
1991
)
FVB/N: An inbred mouse strain preferable for transgenic analysis.
Proc. Natl. Acad. Sci. USA
88
,
2065
2069
Treton
J. A.
,
Jacquemin
E.
,
Courtois
Y.
,
Jeanny
J.-C.
(
1991
)
Differential localization by in situ hybridization of specific crystallin transcripts during mouse lens development.
Differentiation
47
,
143
147
Tripathi
B. J.
,
Tripathi
R. C.
,
Livingston
A. M.
,
Borisuth
N. S. C.
(
1991
)
The role of growth factors in the embryogenesis and differentiation of the eye.
Am. J. Anat
192
,
442
471
Tsutsumi
O.
,
Tsutsumi
A.
,
Oka
T.
(
1967
)
Epidermal growth factor-like, corneal wound healing substances in mouse tears.
J. Clin. Invest
81
,
1067
1071
Wilcox
J. N.
,
Derynck
R.
(
1988
)
Developmental expression of transforming growth factors alpha and beta in mouse fetus.
Mol. Cell. Biol
8
,
3415
3422
Williams
L. R.
,
Satyagal
R. K.
,
Tung
W.
,
Bosselman
R. A.
,
Mendiaz
E. A.
,
Langley
K. E.
(
1990
)
Identification, purification, and biological characterization of hematopoietic stem cell factor from Buffalo rat liver-conditioned medium.
Cell
63
,
195
201
Wilson
S. E.
,
He
Y.-G.
,
Lloyd
S. A.
(
1992
)
EGF, EGF receptor, basic FGF, TGF beta-1, and IL-1 alpha mRNA in human corneal epithelial cells and stromal fibroblasts.
Invest. Ophthalmol. Vis. Sci
33
,
1756
1764
Wilson
S. E.
,
Lloyd
S. A.
(
1991
)
Epidermal growth factor and its receptor, basic fibroblast growth factor, transforming growth factor beta-1, and interleukin-1 alpha messenger RNA production in human corneal endothelial cells.
Invest. Ophthalmol. Vis. Sci
32
,
2747
2755
Witte
O. N.
(
1990
)
Steel locus defines new multipotent growth factor.
Cell
63
,
5
–.
Wong
S. T.
,
Winchell
L. F.
,
McCune
B. K.
,
Earp
H. S.
,
Teixido
J.
,
Massague
J.
,
Herman
B.
,
Lee
D. C.
(
1989
)
The TGF-precursor expressed on the cell surface binds to the EGF receptor on adjacent cells, leading to signal transduction.
Cell
56
,
495
506
Yamamoto
Y.
(
1976
)
Growth of the lens and ocular environment: role of the neural retina in the growth of mouse lens as revealed by an implantation experiment.
Develop. Growth and Differ
18
,
273
278
This content is only available via PDF.