By fractionating conditioned medium (CM) from Drosophila imaginal disc cell cultures, we have identified a family of Imaginal Disc Growth Factors (IDGFs), which are the first polypeptide growth factors to be reported from invertebrates. The active fraction from CM, as well as recombinant IDGFs, cooperate with insulin to stimulate the proliferation, polarization and motility of imaginal disc cells. The IDGF family in Drosophila includes at least five members, three of which are encoded by three genes in a tight cluster. The proteins are structurally related to chitinases, but they show an amino acid substitution that is known to abrogate catalytic activity. It therefore seems likely that they have evolved from chitinases but acquired a new growth-promoting function. The IDGF genes are expressed most strongly in the embryonic yolk cells and in the fat body of the embryo and larva. The predicted molecular structure, expression patterns, and mitogenic activity of these proteins suggest that they are secreted and transported to target tissues via the hemolymph. However, the genes are also expressed in embryonic epithelia in association with invagination movements, so the proteins may have local as well as systemic functions. Similar proteins are found in mammals and may constitute a novel class of growth factors.
Reference
Buhi
W. C.
, Alvarez
I. M.
, Choi
I.
, Cleaver
B. D.
, Simmen
F. A.
(1996
) Molecular cloning and characterization of an estrogen-dependent porcine oviductal secretory glycoprotein.
Biol. Reprod
55
, 1305
–1314
Burke
R.
, Basler
K.
(1996
) Dpp receptors are autonomously required for cell proliferation in the entire developing Drosophila wing.
Development
122
, 2261
–2269
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
Chen
C.
, Jack
J.
, Garofalo
R. S.
(1996
) The Drosophila insulin receptor is required for normal growth.
Endocrinology
137
, 846
–856
Cullen
C. F.
, Milner
M. J.
(1991
) Parameters of growth in primarycultures and cell lines established from Drosophila imaginal discs.
Tissue Cell
23
, 29
–39
Currie
D. A.
, Milner
M. J.
, Evans
C. W.
(1988
) The growth and differentiation in vitro of leg and wing imaginal disc cells from Drosophila melanogaster.
Development
102
, 805
–814
Davis
K. T.
, Shearn
A.
(1977
) In vitro growth of imaginal disks from Drosophila melanogaster.
Science
196
, 438
–440
Denizot
F.
, Lang
R.
(1986
) Rapid colorimetric assay for cell growth and survival: modification to the tetrazolium dye procedure giving improved sensitivity and reliability.
J. Immunol. Methods
89
, 271
–277
Fain
M. J.
, Schneiderman
H. A.
(1979
) Wound healing and regenerative response of fragments of the Drosophila wing imaginal disc cultured in vitro.
J. Insect Physiol
25
, 913
–924
Fernandez-Almonacid
R.
, Rosen
O. M.
(1987
) Structure and ligand specificity of the Drosophila melanogaster insulin receptor.
Molec. Cell. Biol
7
, 2718
–2727
Fernandez
R.
, Tabarini
D.
, Azpiazu
N.
, Frasch
M.
, Schlessinger
J.
(1995
) The Drosophila insulin receptor homolog: a gene essential for embryonic development encodes two receptor isoforms with different signaling potential.
EMBO J
14
, 3373
–3384
Garofalo
R. S.
, Rosen
O. M.
(1988
) Tissue localization of Drosophila melanogaster insulin receptor transcripts during development.
Molec. Cell. Biol
8
, 1638
–1647
Gelbart
W. M.
(1989
) The decapentaplegic gene: a TGF-beta homologue controlling pattern formation in Drosophila.
Development
107
, 65
–74
Hakala
B. E.
, White
C.
, Recklies
A. D.
(1993
) Human cartilage gp-39, a major secretory product of articular chondrocytes and synovial cells, is a mammalian member of a chitinase protein family.
J. Biol. Chem
268
, 25803
–25810
Hu
B.
, Trinh
K.
, Figueira
W. F.
, Price
P. A.
(1996
) Isolation and sequence of a novel human chondrocyte protein related to mammalian members of the chitinase protein family.
J. Biol. Chem
271
, 19415
–19420
Kanost
M. R.
, Zepp
M. K.
, Ladendorff
N. E.
, Andersson
L. A.
(1994
) Isolation and characterization of a hemocyte aggregation inhibitor from hemolymph of Manduca sexta larvae.
Arch. Insect Biochem. Physiol
27
, 123
–136
Kirkpatrick
R. B.
, Matico
R. E.
, McNulty
D. E.
, Strickler
J. E.
, Rosenberg
M.
(1995
) An abundantly secreted glycoprotein from Drosophila melanogaster is related to mammalian secretory proteins produced in rheumatoid tissues and by activated macrophages.
Gene
153
, 147
–154
Kramer
K. J.
, Corpuz
L.
, Choi
H. K.
, Muthukrishnan
S.
(1993
) Sequence of a cDNA and expression of the gene encoding epidermal and gut chitinases of Manduca sexta.
Insect Biochem. Mol. Biol
23
, 691
–701
Lowry
O. H.
, Rosebrough
N. J.
, Farr
A. L.
, Randall
R. J.
(1951
) Protein measurement with the phenol reagent.
J. Biol. Chem
193
, 265
–275
Marin-Hincapie
M.
, Garofalo
R. S.
(1995
) Drosophila insulin receptor: lectin-binding properties and a role for oxidation-reduction of receptor thiols in activation.
Endocrinology
136
, 2357
–2366
Meneses
P.
, De Los Angeles Ortiz
M.
(1975
) A protein extract from Drosophila melanogaster with insulin-like activity.
Comp. Biochem. Physiol. A
51
, 483
–485
Morrison
B. W.
, Leder
P.
(1994
) neu and ras initiate murine mammary tumors that share genetic markers generally absent in c-myc and int-2-initiated tumors.
Oncogene
9
, 3417
–3426
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
Neumann
C. J.
, Cohen
S. M.
(1996
) Distinct mitogenic and cell fate specification functions of wingless in different regions of the wing.
Development
122
, 1781
–1789
Nishida
Y.
, Hata
M.
, Nishizuka
Y.
, Rutter
W. J.
, Ebina
Y.
(1986
) Cloning of a Drosophila cDNA encoding a polypeptide similar to the human insulin receptor precursor.
Biochem. Biophys. Res. Commun
141
, 474
–481
Peel
D. J.
, Johnson
S. A.
, Milner
M. J.
(1990
) The ultrastructure of imaginal disc cells in primary cultures and during cell aggregation in continuous cell lines.
Tissue Cell
22
, 749
–758
Peifer
M.
, Rauskolb
C.
, Williams
M.
, Riggleman
B.
, Wieschaus
E.
(1991
) The segment polarity gene armadillo interacts with the wingless signaling pathway in both embryonic and adult pattern formation.
Development
111
, 1029
–1043
Petruzzelli
L.
, Herrera
R.
, Arenas-Garcia
R.
, Fernandez
R.
, Birnbaum
M. J.
, Rosen
O. M.
(1986
) Isolation of a Drosophila genomic sequence homologous to the kinase domain of the human insulin receptor and detection of the phosphorylated Drosophila receptor with an anti-peptide antibody.
Proc. Natl. Acad. Sci. USA
83
, 4710
–4714
Petruzzelli
L.
, Herrera
R.
, Garcia-Arenas
R.
, Rosen
O. M.
(1985
) Acquisition of insulin-dependent protein tyrosine kinase activity during Drosophila embryogenesis.
J. Biol. Chem
260
, 16072
–16075
Pignoni
F.
, Zipursky
S. L.
(1997
) Induction of Drosophila eye development by decapentaplegic.
Development
124
, 271
–278
Renkema
G. H.
, Boot
R. G.
, Au
F. L.
, Donker-Koopman
W. E.
, Strijland
A.
, Muijsers
A. O.
, Hrebicek
M.
, Aerts
J. M.
(1998
) Chitotriosidase, a chitinase, and the 39-kDa human cartilage glycoprotein, a chitin-binding lectin, are homologues of family 18 glycosyl hydrolases secreted by human macrophages.
Eur. J. Biochem
251
, 504
–509
Ruan
Y.
, Chen
C.
, Cao
Y.
, Garofalo
R. S.
(1995
) The Drosophila insulin receptor contains a novel carboxyl-terminal extension likely to play an important role in signal transduction.
J. Biol. Chem
270
, 4236
–4243
Schweitzer
R.
, Shaharabany
M.
, Seger
R.
, Shilo
B. Z.
(1995
) Secreted Spitz triggers the DER signaling pathway and is a limiting component in embryonic ventral ectoderm determination.
Genes Dev
9
, 1518
–1529
Seecof
R. L.
, Dewhurst
S.
(1974
) Insulin is a Drosophila hormone and acts to enhance the differentiation of embryonic Drosophila cells.
Cell Differ
3
, 63
–70
Shackelton
L. M.
, Mann
D. M.
, Millis
A. J.
(1995
) Identification of a 38-kDa heparin-binding glycoprotein (gp38k) in differentiating vascular smooth muscle cells as a member of a group of proteins associated with tissue remodeling.
J. Biol. Chem
270
, 13076
–13083
Shields
G.
, Sang
J. H.
(1970
) Characteristics of five cell types appearing during in vitro culture of embryonic material from Drosophila melanogaster.
J. Embryol. Exp. Morphol
23
, 53
–69
Shilo
B.-Z.
(1992
) Roles of receptor tyrosine kinases in Drosophila development.
FASEB J
6
, 2915
–2922
Sweeton
D.
, Parks
S.
, Costa
M.
, Wieschaus
E.
(1991
) Gastrulation in Drosophila: The formation of the ventral furrow and posterior midgut invaginations.
Dev
112
, 775
–789
Theisen
H.
, Haerry
T. E.
, O'Connor
M. B.
, Marsh
J. L.
(1996
) Developmental territories created by mutual antagonism between Wingless and Decapentaplegic.
Development
122
, 3939
–3948
Verheijden
G. F.
, Rijnders
A. W.
, Bos
E.
, Coenen-de Roo
C. J.
, van Staveren
C. J.
, Miltenburg
A. M.
, Meijerink
J. H.
, Elewaut
D.
, de Keyser
F.
, Veys
E.
, Boots
A. M.
(1997
) Human cartilage glycoprotein-39 as a candidate autoantigen in rheumatoid arthritis.
Arthritis Rheum
40
, 1115
–1125
Watanabe
T.
, Kobori
K.
, Miyashita
K.
, Fujii
T.
, Sakai
H.
, Uchida
M.
, Tanaka
H.
(1993
) Identification of glutamic acid 204 and aspartic acid 200 in chitinase A1 of Bacillus circulans WL-12 as essential residues for chitinase activity.
J. Biol. Chem
268
, 18567
–18572
Webb
N. R.
, Summers
M. D.
(1990
) Expression of proteins using recombinant baculoviruses.
Techn
2
, 173
–188
This content is only available via PDF.
© 1999 by Company of Biologists
1999
-DevMeetingLivestream.png?versionId=4002)
(update)-InPreprints.png?versionId=4002)
-TechniquesAndResources.png?versionId=4002)
-AmanHusbands.png?versionId=4002)
-NodeNetwork.png?versionId=4002)
