Surgically fragmented Drosophila appendage primordia (imaginal discs) engage in wound healing and pattern regulation during short periods of in vivo culture. Prothoracic leg disc fragments possess exceptional regulative capacity, highlighted by the ability of anterior cells to convert to posterior identity and establish a novel posterior compartment. This anterior/posterior conversion violates developmental lineage restrictions essential for normal growth and patterning of the disc, and thus provides an ideal model for understanding how cells change fate during epimorphic pattern regulation. Here we present evidence that the secreted signal encoded by hedgehog directs anterior/posterior conversion by activating the posterior-specific transcription factor engrailed in regulating anterior cells. In the absence of hedgehog activity, prothoracic leg disc fragments fail to undergo anterior/posterior conversion, but can still regenerate missing anterior pattern elements. We suggest that hedgehog-independent regeneration within the anterior compartment (termed integration) is mediated by the positional cues encoded by wingless and decapentaplegic. Taken together, our results provide a novel mechanistic interpretation of imaginal disc pattern regulation and permit speculation that similar mechanisms could govern appendage regeneration in other organisms.

Reference

Abbott
L. C.
,
Karpen
G. H.
,
Schubiger
G.
(
1981
)
Compartmental restrictions and blastema formation during pattern regulation in Drosophila imaginal leg discs.
Dev. Biol
87
,
64
75
Basler
K.
,
Struhl
G.
(
1994
)
Compartment boundaries and the control of Drosophila limb pattern by hedgehog protein.
Nature
368
,
208
214
Blair
S. S.
(
1992
)
Engrailed expression in the anterior lineage compartment of the developing wing blade of Drosophila.
Development
115
,
21
33
Blair
S. S.
(
1995
)
Compartments and appendage development in Drosophila.
BioEssays
17
,
299
309
Brand
A. H.
,
Perrimon
N.
(
1993
)
Targeted gene expression as a means of altering cell fates and generating dominant phenotypes.
Development
118
,
401
415
Brook
W. J.
,
Cohen
S. M.
(
1996
)
Antagonistic interactions between wingless and decapentaplegic responsible for dorsal-ventral pattern in the Drosophila leg.
Science
273
,
1373
1377
Bryant
P. J.
(
1971
)
Regeneration and duplication following operations in situ on the imaginal discs of Drosophilamelanogaster.
Dev. Biol
26
,
637
651
Campbell
G.
,
Tomlinson
A.
(
1995
)
Initiation of the proximodistal axis in insect legs.
Development
121
,
619
628
Capdevila
J.
,
Estrada
M. P.
,
Sánchez-Herrero
E.
,
Guerrero
I.
(
1994
)
The Drosophila segment polarity gene patched interacts with decapentaplegic in wing development.
EMBO J
13
,
71
82
Couso
J. P.
,
Bate
M.
,
Martinez-Arias
A.
(
1993
)
A wingless-dependent polar coordinate system in Drosophila imaginal discs.
Science
259
,
484
489
Crick
F. H. C.
,
Lawrence
P. A.
(
1975
)
Compartments and polyclones in insect development.
Science
189
,
340
347
de Celis
J. F.
,
Ruiz Gomez
M.
(
1995
)
groucho and hedgehog regulate engrailed expression in the anterior compartment of the Drosophila wing.
Development
121
,
3467
3476
Diaz-Benjumea
F. J.
,
Cohen
B.
,
Cohen
S. M.
(
1994
)
Cell interaction between compartments establishes the proximal-distal axis of Drosophila legs.
Nature
372
,
175
179
Domínguez
M.
,
Brunner
M.
,
Hafen
E.
,
Basler
K.
(
1996
)
Sending and receiving the hedgehog signal: control by the Drosophila Gli protein Cubitus interruptus.
Science
272
,
1621
1625
Ephrussi
B.
,
Beadle
G. W.
(
1936
)
A technique of transplantation for Drosophila.
(1936). Am. Nat
79
,
218
225
Fietz
M. J.
,
Concordet
J. P.
,
Barbosa
R.
,
Johnson
R.
,
Krauss
S.
,
McMahon
A. P.
,
Tabin
C.
,
Ingham
P. W.
(
1994
)
The hedgehog gene family in Drosophila and vertebrate development.
Development
1994
,
43
51
French
V.
,
Bryant
P. J.
,
Bryant
S. V.
(
1976
)
Pattern regulation in epimorphic fields.
Science
193
,
969
981
Garcia-Bellido
A.
,
Ripoll
R.
,
Morata
G.
(
1973
)
Developmental compartmentalization of the wing disc of Drosophila.
Nature New Biol
245
,
251
253
Gehring
W. J.
(
1967
)
Clonal analysis of determination dynamics in cultures of imaginal discs in Drosophilamelanogaster.
Dev. Biol
16
,
438
456
Gelbart
W. M.
(
1989
)
The decapentaplegic gene: a TGF-beta homologue controlling pattern formation in Drosophila.
Development
107
,
65
74
Girton
J. R.
,
Russell
M. A.
(
1980
)
A clonal analysis of pattern duplication in a temperature-sensitive cell-lethal mutant of Drosophila melanogaster.
Dev. Biol
77
,
1
21
Girton
J. R.
,
Russell
M. A.
(
1981
)
An analysis of compartmentalization in pattern duplications Induced by a cell-lethal mutation in Drosophila.
Dev. Biol
85
,
55
64
González
F.
,
Swales
L.
,
Bejsovec
A.
,
Skaer
H.
,
Martinez-Arias
A.
(
1991
)
Secretion and movement of wingless protein in the epidermis of the Drosophila embryo.
Mech. Dev
35
,
43
54
Graves
B. J.
,
Schubiger
G.
(
1982
)
Cell cycle changes during growth and differentiation of imaginal leg discs in Drosophilamelanogaster.
Dev. Biol
93
,
104
110
Guillen
I.
,
Mullor
J. L.
,
Capdevila
J.
,
Sanchez-Herrero
E.
,
Morata
G.
,
Guerrero
I.
(
1995
)
The function of engrailed and the specification of Drosophila wing pattern.
Development
121
,
3447
3456
Hadorn
E.
(
1965
)
Problems of determination and transdetermination.
Brookhaven Symp. Biol
18
,
148
161
Imokawa
Y.
,
Yoshizato
K.
(
1997
)
Expression of Sonic hedgehog gene in regenerating newt limb blastemas recapitulates that in developing limb buds.
Proc. Natl. Acad. Sci. USA
94
,
9159
9164
Ingham
P. W.
,
Baker
N. E.
,
Martinez-Arias
A.
(
1988
)
Regulation of segment polarity genes in the Drosophila blastoderm by fushi tarazu and even skipped.
Nature
331
,
73
75
Jiang
J.
,
Struhl
G.
(
1996
)
Complementary and mutually exclusive activities of decapentaplegic and wingless organize axial patterning during Drosophila leg development.
Cell
86
,
401
409
Johnston
L. A.
,
Schubiger
G.
(
1996
)
Ectopic expression of wingless in imaginal discs interferes with decapentaplegic expression and alters cell determination.
Development
122
,
3519
3529
Kiehle
C. P.
,
Schubiger
G.
(
1985
)
Cell proliferation changes during pattern regulation in imaginal leg discs of Drosophila melanogaster.
Dev. Biol
109
,
336
346
Kondo
S.
(
1992
)
A mechanistic model for morphogenesis and regeneration of limbs and imaginal discs.
Mech. Dev
39
,
161
170
Kornberg
T.
,
Siden
I.
,
O'Farrell
P.
,
Simon
M.
(
1985
)
The engrailed locus of Drosophila: in situ localization of transcripts reveals compartment-specific expression.
Cell
40
,
45
53
Lawrence
P. A.
,
Stuhl
G.
(
1996
)
Morphogens, compartments and pattern: lessons from Drosophila?.
Cell
85
,
951
961
Lecuit
T.
,
Cohen
S. M.
(
1997
)
Proximal-distal axis formation in the Drosophila leg.
Nature
388
,
139
145
Lee
J. J.
,
von Kessler
D. P.
,
Parks
S.
,
Beachy
P. A.
(
1992
)
Secretion and localized transcription suggest a role in positional signaling for products of the segmentation gene hedgehog.
Cell
71
,
33
50
Lepage
T.
,
Cohen
S. M.
,
Diaz-Benjumea
F. J.
,
Parkhurst
S. M.
(
1995
)
Signal transduction by cAMP-dependent protein kinase A in Drosophila limb patterning.
Nature
373
,
711
715
Ma
C.
,
Zhou
Y.
,
Beachy
P. A.
,
Moses
K.
(
1993
)
The segment polarity gene hedgehog is required for progression of the morphogenetic furrow in the developing Drosophila eye.
Cell
75
,
927
938
Masucci
J. D.
,
Miltenberger
R. J.
,
Hoffmann
F. M.
(
1990
)
Pattern-specific expression of the Drosophila decapentaplegic gene in imaginal disks is regulated by 3′ cis-regulatory elements.
Genes Dev
4
,
2011
2023
Maschat
F.
,
Serrano
N.
,
Randsholt
N.
,
Geraud
G.
(
1998
)
engrailed and polyhomeotic interactions are required to maintain the A/P boundary of the Drosophila developing wing.
Development
125
,
2771
2780
Maves
L.
,
Schubiger
G.
(
1995
)
Wingless induces transdetermination in developing Drosophila imaginal discs.
Development
121
,
1263
1272
Maves
L.
,
Schubiger
G.
(
1998
)
A molecular basis for transdetermination in Drosophila imaginal discs: interactions between wingless and decapentaplegic signaling.
Development
125
,
115
24
Maves
L.
,
Schubiger
G.
(
1998
)
Cell Determination and Transdetermination in Drosophila Imaginal Discs.
Current Topics in Developmental Biology
43
,
115
151
Meinhardt
H.
(
1983
)
Cell determination boundaries as organizing regions for secondary embryonic fields.
Dev. Biol
96
,
375
385
Mullor
J. L.
,
Calleja
M.
,
Capdevila
J.
,
Guerrero
I.
(
1997
)
Hedgehog activity, independent of decapentaplegic, participates in wing disc patterning.
Development
124
,
1227
1237
Nellen
D.
,
Burke
R.
,
Struhl
G.
,
Basler
K.
(
1996
)
Direct and long-range action of a DPP morphogen gradient.
Cell
85
,
357
368
Neufeld
T. P.
,
de la Cruz
A. F.
,
Johnston
L. A.
,
Edgar
B. A.
(
1998
)
Coordination of growth and cell division in the Drosophila wing.
Cell
93
,
1183
1193
Penton
A.
,
Hoffmann
F. M.
(
1996
)
Decapentaplegic restricts the domain of wingless during Drosophila limb patterning.
Nature
382
,
162
164
Pignoni
F.
,
Zipursky
S.
(
1997
)
Induction of Drosophila eye development by decapentaplegic.
Development
124
,
271
278
Raftery
L. A.
,
Sanicola
M.
,
Blackman
R. K.
,
Gelbart
W. M.
(
1991
)
The relationship of decapentaplegic and engrailed expression in Drosophila imaginal disks: do these genes mark the anterior-posterior compartment boundary?.
Development
113
,
27
33
Reinhardt
C. A.
,
Hodgkin
N. M.
,
Bryant
P. J.
(
1977
)
Wound healing in the imaginal discs of Drosophila. I. Scanning electron microscopy of normal and healing wing discs.
Dev. Biol
60
,
238
257
Riddle
R. D.
,
Johnson
R. L.
,
Laufer
E.
,
Tabin
C.
(
1993
)
Sonic hedgehog mediates the polarizing activity of the ZPA.
Cell
75
,
1401
1416
Schubiger
G.
(
1971
)
Regeneration, Duplication and Transdetermination in fragments of the leg disc of Drosophila melanogaster.
Dev. Biol
26
,
277
295
Struhl
G.
,
Barbash
D. A.
,
Lawrence
P. A.
(
1997
)
Hedgehog organises the pattern and polarity of epidermal cells in the Drosophila abdomen.
Development
124
,
2143
54
Struhl
G.
,
Basler
K.
(
1993
)
Organizing activity of Wingless protein in Drosophila.
Cell
72
,
527
540
Tabata
T.
,
Eaton
S.
,
Kornberg
T. B.
(
1992
)
The Drosophila hedgehog gene is expressed in specifically in posterior compartment cells and is a target of engrailed regulation.
Genes Dev
6
,
2635
2645
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
van den Heuvel
M.
,
Nusse
R.
,
Johnston
P.
,
Lawrence
P. A.
(
1989
)
Distribution of the wingless gene product in Drosophila embryos: a protein involved in cell-cell communication.
Cell
59
,
739
749
Zecca
M.
,
Basler
K.
,
Struhl
G.
(
1996
)
Direct and long-range action of a Wingless morphogen gradient.
Cell
87
,
833
844
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