Fibroblast growth factors (FGFs), such as FGF-1, have been shown to induce differentiation of lens epithelial cells both in tissue culture and in transgenic mice. In the present study, using the alpha A-crystallin promoter, we generated transgenic mice that express different FGFs (FGF-4, FGF-7, FGF-8, FGF-9) specifically in the lens. All four FGFs induced changes in ocular development. Microphthalmic eyes were evident in transgenic mice expressing FGF-8, FGF-9 and some lines expressing FGF-4. A developmental study of the microphthalmic eyes revealed that, by embryonic day 15, expression of these FGFs induced lens epithelial cells to undergo premature fiber differentiation. In less severely affected lines expressing FGF-4 or FGF-7, the lens epithelial cells exhibited a premature exit from the cell cycle and underwent a fiber differentiation response later in development, leading to cataract formation. The responsiveness of lens cells to different FGFs indicates that these proteins stimulate the same or overlapping downstream signalling pathway(s). These overlapping effects of different FGFs on a common cell type indicate that the normal developmental roles for these genes are determined by the temporal and spatial regulation of their expression patterns. The fact that any of these FGFs can induce ocular defects and loss of lens transparency implies that it is essential for the normal eye to maintain very specific spatial control over FGF expression in order to prevent cataract induction.
REFERENCES
Amaya
E.
, Musci
T. J.
, Kirschner
M.
(1991
) Expression of a dominant negative mutant of the FGF receptor disrupts mesoderm formation in Xenopus embryos.
Cell
66
, 257
–270
Baird
A.
(1994
) Fibroblast growth factors: activities and significance of non-neurotrophin neurotrophic growth factors.
Curr. Opin. Neurobiol
4
, 78
–86
Basilico
C.
, Moscatelli
D.
(1992
) The FGF family of growth factors and oncogenes.
Adv. Cancer Res
59
, 115
–165
Bellot
F.
, Crumley
G.
, Kaplow
J. M.
, Schlessinger
J.
, Jaye
M.
, Dionne
C. A.
(1991
) Ligand-induced transphosphorylation between different FGF receptors.
EMBO J
10
, 2849
–2854
Burgess
W. H.
, Maciag
T.
(1989
) The heparin-binding (fibroblast) growth factor family of proteins.
Annu. Rev. Biochem
58
, 575
–606
Chamberlain
C. G.
, McAvoy
J. W.
(1989
) Induction of lens fibre differentiation by acidic and basic fibroblast growth factor (FGF).
Growth Factors
1
, 125
–134
Chellaiah
A. T.
, McEwan
D. G.
, Werner
S.
, Xu
J.
, Ornitz
D. M.
(1994
) Alternative splicing in immunoglobulin-like domain III creates a receptor highly specific for acidic FGF/FGF-1.
J. Biol. Chem
269
, 11620
–11627
Chow
R. L.
, Roux
G. D.
, Roghani
M.
, Palmer
M. A.
, Rifkin
D. B.
, Moscatelli
D. A.
, Lang
R. A.
(1995
) FGF suppresses apoptosis and induces differentiation of fibre cells in the mouse lens.
Development
121
, 4383
–4393
Colvin
J. S.
, Bohne
B. A.
, Harding
G. W.
, McEwen
D. G.
, Ornitz
D. M.
(1996
) Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3.
Nature Genetics
12
, 390
–397
Coulier
F.
, Pontarotti
P.
, Roubin
R.
, Hartung
H.
, Goldfarb
M.
, Birnbaum
D.
(1997
) Of worms and men: an evolutionary perspective on the fibroblast growth factor (FGF) and FGF receptor families.
J. Mol. Evol
44
, 43
–56
Crossley
P. H.
, Martin
G. R.
(1995
) The mouse Fgf8 gene encodes a family of polypeptides and is expressed in regions that direct outgrowth and patterning in the developing embryo.
Development
121
, 439
–451
de Iongh
R.
, McAvoy
J.W.
(1992
) Distribution of acidic and basic fibroblast growth factors (FGF) in the foetal rat eye: implications for lens development.
Growth Factors
6
, 159
–177
de Iongh
R.
, McAvoy
J.W.
(1993
) Spatio-temporal distribution of acidic and basic FGF indicates a role for FGF in rat lens morphogenesis.
Dev. Dynam
198
, 190
–202
de Iongh
R. U.
, Lovicu
F. J.
, Hanneken
A.
, Baird
A.
, McAvoy
J. W.
(1996
) FGF receptor-1 (flg) expression is correlated with fibre differentiation during rat lens morphogenesis and growth.
Dev. Dynam
206
, 412
–426
de Iongh
R. U.
, Lovicu
F. J.
, Chamberlain
C. G.
, McAvoy
J. W.
(1997
) Differential expression of FGF receptors during rat lens morphogenesis and growth.
Invest. Ophthalmol. Vis. Sci
38
, 1688
–1699
Deng
C.
, Wynshaw-Boris
A.
, Shen
M. M.
, Daugherty
C.
, Ornitz
D. M.
, Leder
P.
(1994
) Murine FGFR-1 is required for early postimplantation growth and axial organization.
Genes Dev
8
, 3045
–3057
Deng
C.
, Wynshaw-Boris
A.
, Zhou
F.
, Kuo
A.
, Leder
P.
(1996
) Fibroblast growth factor receptor 3 is a negative regulator of bone growth.
Cell
84
, 911
–921
Feldman
B.
, Poueymirou
W.
, Papaioannou
V. E.
, De Chiara
T. M.
, Goldfarb
M.
(1995
) Requirement of FGF-4 for postimplantation mouse development.
Science
276
, 246
–249
Givol
D.
, Yayon
A.
(1992
) Complexity of FGF receptors: genetic basis for structural diversity and functional specificity.
FASEB J
6
, 3362
–3369
Green
P. J.
, Walsh
F. S.
, Doherty
P.
(1996
) Promiscuity of fibroblast growth factor receptors.
BioEssays
18
, 639
–646
Guo
L.
, Yu
Q.-C.
, Fuchs
E.
(1993
) Targeting expression of keratinocyte growth factor to keratinocytes elicits striking changes in epithelial differentiation in transgenic mice.
EMBO J
12
, 973
–986
Guo
L.
, Degenstein
L.
, Fuchs
E.
(1995
) Keratinocyte growth factor is required for hair development but not for wound healing.
Genes Dev
10
, 165
–175
Hebert
J. M.
, Basilico
C.
, Goldfarb
M.
, Haub
O.
, Martin
G. R.
(1990
) Isolation of cDNAs encoding four mouse FGF family members and characterization of their expression patterns during embryogenesis.
Dev. Biol
138
, 454
–463
Hebert
J.
, Rosenquist
T.
, Gotz
J.
, Martin
G. R.
(1994
) FGF-5 as a regulator of hair growth cycle: evidence from targeted and spontaneous mutations.
Cell
78
, 1
–20
Hecht
D.
, Zimmerman
N.
, Bedford
M.
, Avivi
A.
, Yayon
A.
(1995
) Identification of fibroblast growth factor 9 (FGF9) as a high affinity, heparindependent ligand for FGF receptors 3 and 2 but not for FGF receptors 1 and 4.
Growth Factors
12
, 223
–233
Hoshikawa
M.
, Ohbayashi
N.
, Yonamine
A.
, Konishi
M.
, Ozaki
K.
, Fukui
S.
, Itoh
N.
(1998
) Structure and expression of a novel fibroblast growth factor, FGF-17, preferentially expressed in the embryonic brain.
Biochem. Biophys. Res. Comm
244
, 187
–191
Johnson
D. E.
, Williams
L. T.
(1993
) Structural and functional diversity in the FGF receptor multigene family.
Adv. Cancer Res
60
, 1
–41
Kinoshita
N.
, Minshull
J.
, Kirschner
M. W.
(1995
) The identification of two novel ligands of the FGF receptor by a yeast screening method and their activity in Xenopus development.
Cell
83
, 621
–630
Kitaoka
T.
, Aotaki-Keen
A. E.
, Hjelmeland
L. M.
(1994
) Distribution of FGF-5 in the rhesus macaque retina.
Invest. Ophthalmol. Vis. Sci
35
, 3189
–3198
Kozak
M.
(1991
) Structural features in eukaryotic mRNAs that modulate the initiation of translation.
J. Biol. Chem
266
, 19867
–19870
Ledoux
D.
, Gannon-Zaki
L.
, Barritault
D.
(1992
) Interactions of FGFs with target cells.
Prog. Growth Factor Res
4
, 107
–120
Lovicu
F. J.
, McAvoy
J. W.
(1993
) Immunolocalization of acidic FGF, basic FGF and heparan sulfate proteoglycan in the rat lens: implications for lens polarity and growth patterns.
Invest. Ophthalmol. Vis. Sci
34
, 3355
–3365
Lovicu
F. J.
, de Iongh
R.
, McAvoy
J. W.
(1997
) Expression of FGF-1 and FGF-2 mRNA during lens morphogenesis, differentiation and growth.
Curr. Eye Res
16
, 222
–230
MacArthur
C. A.
, Lawshe
A.
, Xu
J.
, Santos-Ocampo
S.
, Heikinheimo
M.
, Chellaiah
A. T.
, Ornitz
D. M.
(1995
) FGF-8 isoforms activate receptor splice forms that are expressed in mesenchymal regions of mouse development.
Development
121
, 3603
–3613
MacArthur
C. G.
, Lawshe
A.
, Xu
J.
, Shankar
D. B.
, Heikinheimo
M.
, Shackleford
G. M.
(1995
) FGF-8 isoforms differ in NIH3T3 cell transforming potential.
Cell. Growth Diff
6
, 817
–825
Mansour
S. L.
, Goddard
J. M.
, Capecchi
M. R.
(1993
) Mice homozygous for a targeted disruption of the proto-oncogene int-2 have developmental defects in the tail and inner ear.
Development
117
, 13
–28
Mason
I. J.
, Fuller-Pace
F.
, Smith
R.
, Dickson
C.
(1994
) FGF-7 (keratinocyte growth factor) expression during mouse development suggests roles in myogenesis, forebrain regionalisation and epithelial-mesenchymal interactions.
Mech. Dev
45
, 15
–30
McAvoy
J.W.
, Chamberlain
C. G.
(1989
) Fibroblast growth factor (FGF) induces different responses in lens epithelial cells depending on its concentration.
Development
107
, 221
–228
McAvoy
J. W.
, Chamberlain
C. G.
, de Iongh
R. U.
, Richardson
N. A.
, Lovicu
F. J.
(1991
) The role of fibroblast growth factor in eye lens development.
Ann. N.Y. Acad. Sci
638
, 256
–274
McWhirter
J. R.
, Goulding
M.
, Weiner
J. A.
, Chun
J.
, Murre
C.
(1997
) A novel fibroblast growth factor gene expressed in the developing nervous system is a downstream target of the chimeric homeodomain oncoprotein E2A-Pbx1.
Development
124
, 3221
–3232
Miki
T.
, Bottaro
D. P.
, Fleming
T. P.
, Smith
C. L.
, Burgess
W. H.
, Chan
A. M.-L.
, Aaronson
S. A.
(1992
) Determination of the ligand-binding specificity by alternative splicing: two distinct growth factor receptors encoded by a single gene.
Proc. Natl. Acad. Sci. USA
89
, 246
–250
Miyake
A.
, Konishi
M.
, Martin
F. H.
, Hernday
N. A.
, Ozaki
K.
, Yamamoto
S.
, Mikami
T.
, Arakawa
T.
, Itoh
N.
(1998
) Structure and expression of a novel member, FGF-16, of the fibroblast growth factor family.
Biochem. Biophys. Res. Comm
243
, 148
–152
Miyamoto
M.
, Naruo
K.-I.
, Seko
C.
, Matsumoto
S.
, Kondo
T.
, Kurokawa
T.
(1993
) Molecular cloning of a novel cytokine cDNA encoding the ninth member of the fibroblast growth factor family, which has a unique secretion property.
Mol. Cell. Biol
13
, 4251
–4259
Mohammadi
M. A.
, Honegger
A. M.
, Rotin
D.
, Fisher
R.
, Bellot
F.
, Li
W.
, Dionne
C. A.
, Jaye
M.
, Rubinstein
M.
, Schlessinger
J.
(1991
) A tyrosine-phosphorylated carboxy-terminal peptide of the fibroblast growth factor receptor (flg) is a binding site for the SH2 domain of phospholipase C-1.
Mol. Cell. Biol
11
, 5068
–5078
Nauro
K.-I.
, Seko
C.
, Kuroshima
K.-I.
, Matsutani
E.
, Sasada
R.
, Kondo
T.
, Kurokawa
T.
(1993
) Novel secretory heparin-binding factor from human glioma cells (glia activating factor) involved in glia cell growth.
J. Biol. Chem
268
, 2857
–2864
Olwin
B. B.
, Arthur
K.
, Hannon
K.
, Hein
P.
, McFall
A.
, Riley
B.
, Szebenyi
G.
, Zhou
Z.
, Zuber
M. E.
, Rapraeger
A. C.
, Fallon
J. F.
, Kudla
A. J.
(1994
) Role of FGFs in skeletal muscle and limb development.
Mol. Reprod. Dev
39
, 90
–101
Orr-Urtreger
A.
, Bedford
M. T.
, Burakova
T.
, Arman
E.
, Zimmer
Y.
, Yayon
A.
, Givol
D.
, Lonai
P.
(1993
) Developmental localization of the splicing alternatives of fibroblast growth factor receptor-2.
Dev. Biol
158
, 475
–486
Ornitz
D. M.
, Xu
J.
, Colvin
J. S.
, McEwen
D. G.
, MacArthur
C. A.
, Coulier
F.
, Gao
G.
, Goldfarb
M.
(1996
) Receptor specificity of the fibroblast growth factor family.
J. Biol. Chem
271
, 15292
–15297
Peters
K.
, Ornitz
D.
, Werner
S.
, Williams
L. T.
(1993
) Unique expression pattern of the FGF receptor 3 gene during mouse organogenesis.
Dev Biol
155
, 423
–430
Reneker
L. W.
, Silversides
D. W.
, Patel
K.
, Overbeek
P. A.
(1995
) TGFcan act as a chemoattractant to perioptic mesenchymal cells in developing mouse eyes.
Development
121
, 1669
–1680
Reneker
L. W.
, Overbeek
P. A.
(1996
) Lens-specific expression of PDGF-A alters lens growth and development.
Dev. Biol
180
, 554
–565
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
Robinson
M. L.
, MacMillan-Crow
L. A.
, Thompson
J. A.
, Overbeek
P. A.
(1995
) Expression of a truncated FGF receptor results in defective lens development in transgenic mice.
Development
121
, 3959
–3967
Robinson
M. L.
, Ohtaka-Maruyama
C.
, Chan
C.
, Jamieson
S.
, Dickson
C.
, Overbeek
P. A.
, Chepelinsky
A. B.
(1998
) Disregulation of ocular morphogenesis by lens-specific expression of FGF-3/int-2 in transgenic mice.
Dev. Biol
198
, 13
–31
Rupp
E.
, Siegbahn
A.
, Rönnstrand
L.
, Wernstedt
C.
, Claesson-Welsh
L.
, Heldin
C.-H.
(1994
) A unique autophosphorylation site in the platelet-derived growth factorreceptor from a heterodimeric receptor complex.
Eur. J. Biochem
225
, 29
–41
Saiki
R. K.
, Gelfand
D. H.
, Stoffel
S.
, Scharf
S. J.
, Higuchi
R.
, Horn
G. T.
, Mullis
K. B.
, Erlich
H. A.
(1988
) Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase.
Science
239
, 487
–494
Santos-Ocampo
S.
, Colvin
J. S.
, Chellaiah
A.
, Ornitz
D. M.
(1996
) Expression and biological activity of mouse fibroblast growth factor-9.
J. Biol. Chem
271
, 1726
–1731
Schlessinger
J.
, Ullrich
A.
(1992
) Growth factor signalling by receptor tyrosine kinases.
Neuron
9
, 383
–391
Schneider
J. Q.
, Gu
W.
, Zhu
L.
, Mahdavi
V.
, Nadal-Ginard
B.
(1994
) Reversal of terminal differentiation mediated by p107 in Rb/ muscle cells.
Science
264
, 1467
–1471
Schulz
M.
, Chamberlain
C. G.
, de Iongh
R. U.
, McAvoy
J.W.
(1993
) Acidic and basic FGF in ocular media and lens: implications for lens polarity and growth patterns.
Development
118
, 117
–126
Shi
E.
, Kan
M.
, Xu
J.
, Wang
F.
, Hou
J.
, McKeehan
W. L.
(1993
) Control of fibroblast growth factor receptor kinase signal transduction by heterodimerization of combinatorial splice variants.
Mol. Cell. Biol
13
, 3907
–3918
Smallwood
P. M.
, Munoz-Sanjuan
I.
, Tong
P.
, Macke
J. P.
, Hendry
S. H. C.
, Gilbert
D. J.
, Copeland
N. G.
, Jenkins
N. A.
, Nathans
J.
(1996
) Fibroblast growth factor (FGF) homologous factors: new members of the FGF family implicated in nervous system development.
Proc. Natl. Acad. Sci. USA
93
, 9850
–9857
Song
J.
, Slack
M. W.
(1996
) XFGF-9: a new fibroblast growth factor from Xenopus embryos.
Dev. Dynam
206
, 427
–436
Srinivasan
Y.
, Overbeek
P. A.
(1996
) Expression of lens specific fibroblast growth factor (FGF5) causes altered epithelial cell morphology and degeneration of fiber cells.
ARVO Abstracts. Invest Ophthalmol Vis Sci
37
, 924
–.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 analyses.
Proc. Natl. Acad. Sci. USA
88
, 2065
–2069
Tanaka
A.
, Miyamoto
K.
, Minamino
N.
, Takeda
M.
, Sato
B.
, Matsuo
H.
, Matsumoto
K.
(1992
) Cloning and characterization of an androgen-induced growth factor essential for the androgen-dependent growth of mouse mammary carcinoma cells.
Proc. Natl. Acad. Sci. USA
89
, 8928
–8932
Ueno
H.
, Gunn
M.
, Dell
K.
, Tseng
A.
, Williams
L.
(1992
) A truncated form of fibroblast growth factor receptor 1 inhibits signal transduction by multiple types of fibroblast growth factor receptor.
J. Biol. Chem
267
, 1470
–1476
Werner
S.
, Smola
H.
, Liao
X.
, Longaker
M. T.
, Krieg
T.
, Hans Hofschneider
P.
, Williams
L. T.
(1994
) The function of KGF in morphogenesis of epithelium and reepithelization of wounds.
Science
266
, 819
–822
Wilkinson
D. G.
, Bhatt
S.
, McMahon
A. P.
(1989
) Expression pattern of the FGF-related proto-oncogene int-2 suggests multiple roles in fetal development.
Development
105
, 131
–136
Wilson
S. E.
, Walker
J. W.
, Chwang
E. L.
, He
Y. G.
(1993
) Hepatocyte growth factor, keratinocyte growth factor, their receptors, fibroblast growth factor receptor-2, and the cells of the cornea.
Invest. Ophthalmol. Vis. Sci
34
, 2544
–2561
Xu
X.
, Weinstein
M.
, Li
C.
, Naski
M.
, Cohen
R. I.
, Ornitz
D. M.
, Leder
P.
, Deng
C.
(1998
) Fibroblast growth factor receptor 2 (FGFR2)-mediated reciprocal regulation loop between FGF8 and FGF10 is essential for limb induction.
Development
125
, 753
–765
Yamaguchi
T. P.
, Harpal
K.
, Henkemeyer
M.
, Rossant
J.
(1994
) fgfr-1 is required for embryonic growth and mesodermal patterning during mouse gastrulation.
Genes Dev
8
, 3032
–3044
Yamasaki
M.
, Miyake
A.
, Tagashira
S.
, Itoh
N.
(1996
) Structure and expression of the rat mRNA encoding a novel member of the fibroblast growth factor family.
J. Biol. Chem
271
, 15918
–15921
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