The Drosophila Delta (Dl) gene is essential for cell-cell communication regulating the determination of various cell fates during development. Dl encodes a transmembrane protein, which contains tandem arrays of epidermal-growth-factor-like repeats in the extracellular domain and directly interacts with Notch, another transmembrane protein with similar structural features, in a ligand-receptor-like manner. Similarly, cell-cell interactions involving Delta-like and Notch-like proteins are required for cell fate determinations in C. elegans. Notch homologues were also isolated from several vertebrate species, suggesting that cell-to-cell signaling mediated by Delta- and Notch-like proteins could also underlie cell fate determination during vertebrate development. However, in vertebrates, no Delta homologues have yet been described. We have isolated a novel mouse gene, Dll1 (delta-like gene 1), which maps to the mouse t-complex and whose deduced amino acid sequence strongly suggests that Dll1 represents a mammalian gene closely related to Drosophila Delta. Dll1 is transiently expressed during gastrulation and early organogenesis, and in a tissue-restricted manner in adult animals. Between day 7 and 12.5 of development, expression was detected in the paraxial mesoderm, closely correlated with somitogenesis, and in subsets of cells in the nervous system. In adult animals, transcripts were detected in lung and heart. Dll1 expression in the paraxial mesoderm and nervous system is strikingly similar to the expression of mouse Notch1 during gastrulation and early organogenesis. The overlapping expression patterns of the Dll1 and Notch1 genes suggest that cells in these tissues can communicate by interaction of the Dll1 and Notch1 proteins. Our results support the idea that Delta- and Notch-like proteins are involved in cell-to-cell communication in mammalian embryos and suggest a role for these proteins in cellular interactions underlying somitogenesis and development of the nervous system.

Reference

Altschul
S. F.
,
Gish
W.
,
Miller
W.
,
Myers
E. W.
,
Lipman
D. J.
(
1990
)
Basic local alignment search tool.
J. Molec. Biol
215
,
403
410
Artzt
K.
(
1984
)
Gene mapping within the T/t complex of the mouse. III: t-lethal genes are arranged in three clusters on chromosome 17.
Cell
39
,
565
572
Artzt
K.
,
McCormick
P.
,
Bennett
D.
(
1982
)
Gene mapping within the T/t complex of the mouse. I. t-lethal genes are nonallelic.
Cell
28
,
463
470
Austin
J.
,
Kimble
J.
(
1987
)
glp −1 is required in the germ line for regulation of the decision between mitosis and meiosis in C. elegans.
Cell
51
,
589
599
Basler
K.
,
Edlund
T.
,
Jessell
T. M.
,
Yamada
T.
(
1993
)
Control of cell pattern in the neural tube: regulation of cell differentiation by dorsalin-1, a novel TGFfamily member.
Cell
73
,
687
702
Bennett
D.
(
1975
)
The T-locus of the mouse.
Cell
6
,
441
454
Bennett
D.
,
Dunn
L. C.
(
1960
)
A lethal mutant (tw18) in the house mouse showing partial duplications.
J. Exp. Zool
143
,
203
219
Bierkamp
C.
,
Campos-Ortega
J. A.
(
1993
)
A zebrafish homologue of the Drosophila neurogenic gene Notch and its pattern of transcription during early embryogenesis.
Mech. Dev
43
,
87
100
Breen
M.
,
Deakin
L.
,
Macdonald
B.
,
Miller
S.
,
Sibson
R.
,
Tartellin
E.
,
Avner
P.
,
Bourgade
F.
,
Guenet
J. L.
,
Montagutelli
X.
,
Poirier
C.
,
Simon
D.
,
Tailor
D.
,
Bishop
M.
,
Kelly
M.
,
Rysavy
F.
,
Rastan
S.
,
Norris
D.
,
Shepherd
D.
,
Abbott
C.
(
1994
).
Towards high regulation maps of the mouse and human genomes- a facility for ordering markers to 0.1 cM resolution.
Human Molecular Genetics
3
,
621
627
Búcan
M.
,
Herrmann
B. G.
,
Frischauf
A.
,
Bautch
V. L.
,
Bode
V.
,
Silver
L.
,
Martin
G. L.
,
Lehrach
H.
(
1987
)
Deletion and duplication ofDNA sequences is associated with the embryonic lethal phenotype of the t9complementation group of the mouse t complex.
Genes Dev
1
,
376
385
Chomczynski
P.
,
Sacchi
N.
(
1987
)
Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction.
Anal. Biochemistry
162
,
156
159
Coffman
C.
,
Harris
W.
,
Kintner
C.
(
1990
)
Xotch, the Xenopus homolog of Drosophila Notch.
Science
249
,
1438
1441
Coffman
C. R.
,
Skoglund
P.
,
Harris
W. A.
,
Kintner
C. R.
(
1993
)
Expression of an extracellular deletion of Xotch diverts cell fate in Xenopus-embryos.
Cell
73
,
659
671
Conlon
R. A.
,
Reaume
A. G.
,
Rossant
J.
(
1995
)
Notch1 is required for the coordinate segmentation of somites.
Development
121
,
1533
1545
Corbin
V.
,
Michelson
A. M.
,
Abmayr
S. M.
,
Neel
V.
,
Alcamo
E.
,
Maniatis
T.
,
Young
M. W.
(
1991
)
A role for the Drosophila neurogenic genes in mesoderm differentiation.
Cell
67
,
311
323
Davies
J. A.
,
Cook
G. M.
,
Stern
C. D.
,
Keynes
R. J.
(
1990
)
Isolation from chick somites of a glycoprotein fraction that causes collapse of dorsal root ganglion growth cones.
Neuron
4
,
11
20
Davis
C. G.
(
1990
)
The many faces of epidermal growth factor repeats.
New Biologist
2
,
410
419
del Amo
F. F.
,
Gendron Maguire
M.
,
Swiatek
P. J.
,
Jenkins
N. A.
,
Copeland
N. G.
,
Gridley
T.
(
1993
)
Cloning, analysis, and chromosomal localization of Notch-1, a mouse homolog of Drosophila Notch.
Genomics
15
,
259
264
del Amo
F. F.
,
Smith
D. E.
,
Swiatek
P. J.
,
Gendron Maguire
M.
,
Greenspan
R. J.
,
McMahon
A. P.
,
Gridley
T.
(
1992
)
Expression pattern of Motch, a mouse homolog of Drosophila Notch, suggests an important role in early postimplantation mouse development.
Development
115
,
737
744
Devereux
J.
,
Haeberli
P.
,
Smithies
O.
(
1984
)
A comprehensive set of sequence analysis programs for the VAX.
Nucl. Acid. Res
12
,
387
395
Ellisen
L. W.
,
Bird
J.
,
West
D. C.
,
Soreng
A. L.
,
Reynolds
T. C.
,
Smith
S. D.
,
Sklar
J.
(
1991
)
TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms.
Cell
66
,
649
661
Fehon
R. G.
,
Kooh
P. J.
,
Rebay
I.
,
Regan
C. L.
,
Xu
T.
,
Muskavitch
M. A.
,
Artavanis Tsakonas
S.
(
1990
)
Molecular interactions between the protein products of the neurogenic loci Notch and Delta, two EGF-homologous genes in Drosophila.
Cell
61
,
523
534
Goldstein
R. S.
,
Teillet
M.-A.
,
Kalcheim
C.
(
1990
)
The microenvironment created by grafting rostral half-somites is mitogenic for neural crest cells.
Proc. Natl. Acad. Sci. USA
87
,
4476
4480
Greenwald
I. S.
,
Sternberg
P. W.
,
Horvitz
H. R.
(
1983
)
The lin −12 locus specifies cell fates in Caenorhabditis elegans.
Cell
34
,
435
444
Haenlin
M.
,
Kramatschek
B.
,
Campos-Ortega
J. A.
(
1990
)
The pattern of transcription of the neurogenic gene Delta of Drosophila melanogaster.
Development
110
,
905
914
Hartenstein
A. Y.
,
Rugendorff
A.
,
Tepass
U.
,
Hartenstein
V.
(
1992
)
The function of the neurogenic genes during epithelial development in the Drosophila embryo.
Development
116
,
1203
1220
Heitzler
P.
,
Simpson
P.
(
1993
)
Altered epidermal growth factor-like sequences provide evidence for a role of Notch as a receptor in cell fate decisions.
Development
117
,
1113
1123
Hogan
B.
,
Holland
P.
,
Schofield
P.
(
1985
)
How is the mouse segmented?.
Trends Genetics
1
,
67
74
Huarte
J.
,
Stutz
A.
,
O'Connell
M. L.
,
Gubler
P. D.
,
Belin
D.
,
Darrow
A. L.
,
Strickland
S.
,
Vassalli
J. D.
(
1992
)
Tansient Translation Silencing by Reverse mRNA Deadenylation.
Cell
69
,
1021
1130
Keynes
R. J.
,
Stern
C. D.
(
1984
)
Segmentation in the vertebrate nervous system.
Nature
310
,
786
789
Kopczynski
C. C.
,
Alton
A. K.
,
Fechtel
K.
,
Kooh
P. J.
,
Muskavitch
M. A.
(
1988
)
Delta, a Drosophila neurogenic gene, is transcriptionally complex and encodes a protein related to blood coagulation factors and epidermal growth factor of vertebrates.
Genes Dev
2
,
1723
1735
Laborda
J.
,
Sausville
E. A.
,
Hoffman
T.
,
Notario
V.
(
1993
)
dlk, a putative mammalian homeotic gene differentially expressed in small cell lung carcinoma and neuroendocrine tumor cell line.
J. Biol. Chem
268
,
6
–.
Lardelli
M.
,
Dahlstrand
J.
,
Lendahl
U.
(
1994
)
The novel Notchhomologue mouse Notch 3 lacks specific epidermal growth factor-repeats and is expressed in proliferating neuroepithelium.
Mech. Dev
46
,
123
136
Lardelli
M.
,
Lendahl
U.
(
1993
)
Motch A and motch B--two mouse Notch homologues coexpressed in a wide variety of tissues.
Exp. Cell Res
204
,
2
–.
Lieber
T.
,
Wesley
C. S.
,
Alcamo
E.
,
Hassel
B.
,
Krane
J. F.
,
Campos-Ortega
J. A.
,
Young
M. W.
(
1992
)
Single amino acid substitutions in EGF-like elements of Notch and Delta modify Drosophila development and affect cell adhesion in vitro.
Neuron
9
,
847
859
Lindsell
C. E.
,
Shawber
C. J.
,
Boulter
J.
,
Weinmaster
G.
(
1995
)
Jagged: A Mammalian Ligand That Activates Notch1.
Cell
80
,
909
917
Mello
C. C.
,
Draper
B. W.
,
Priess
J. R.
(
1994
)
The maternal genes apx-1 and glp-1 and establishment of dorsal-ventral polarity in the early C. elegans embryo.
Cell
77
,
95
106
Moser
G. C.
,
Gluecksohn-Waelsch
S.
(
1967
)
Developmental genetics of a recessive allele at the complex T-locus in the mouse.
Dev. Biol
16
,
564
576
Muskavitch
M. A.
(
1994
)
Delta-notch signaling and Drosophila cell fate choice.
Dev. Biol
166
,
415
430
Muskavitch
M. A.
,
Hoffmann
F. M.
(
1990
)
Homologs of vertebrate growth factors in Drosophila melanogaster and other invertebrates.
Curr. Top. Dev. Biol
24
,
289
328
Placzek
M.
,
Yamada
T.
,
Tessierlavigne
M.
,
Jessell
T.
,
Dodd
J.
(
1991
)
Control of dorsoventral pattern in vertebrate neural development-induction and polarizing properties of the floor plate.
Development
113
,
105
122
Reaume
A. G.
,
Conlon
R. A.
,
Zirngibl
R.
,
Yamaguchi
T. P.
,
Rossant
J.
(
1992
)
Expression analysis of a Notch homologue in the mouse embryo.
Dev. Biol
154
,
377
387
Rebay
I.
,
Fleming
R. J.
,
Fehon
R. G.
,
Cherbas
L.
,
Cherbas
P.
,
Artavanis Tsakonas
S.
(
1991
)
Specific EGF repeats of Notch mediate interactions with Delta and Serrate: implications for Notch as a multifunctional receptor.
Cell
67
,
687
699
Shaw
G.
,
Kamen
R.
(
1986
)
A conserved AU sequence from the 3untranslated region of GM-CSF mRNA mediates selective mRNA degradation.
Cell
46
,
659
667
Smas
C. M.
,
Sul
H. S.
(
1993
)
Pref-1, a protein containing EGF-like repeats, inhibits adipocyte differentiation.
Cell
73
,
725
734
Swiatek
P. J.
,
Lindsell
C. E.
,
Delamo
F. F.
,
Weinmaster
G.
,
Gridley
T.
(
1994
)
Notch1 is essential for postimplantation development in mice.
Genes Dev
8
,
707
719
Tax
F. E.
,
Yeargers
J. J.
,
Thomas
J. H.
(
1994
)
Sequence of C. elegans lag-2 reveals a cell-signalling domain shared with Delta and Serrate of Drosophila.
Nature
368
,
150
154
Technau
G. M.
,
Campos-Ortega
J. A.
(
1987
)
Cell autonomy of expression of neurogenic genes of Drosophila melanogaster.
Proc. Natl Acad. Sci. USA
84
,
4500
4504
Tepass
U.
,
Hartenstein
V.
(
1995
)
Neurogenic and proneural genes control cell fate specification in the Drosophila endoderm.
Development
121
,
393
405
Vässin
H.
,
Bremer
K. A.
,
Knust
E.
,
Campos-Ortega
J. A.
(
1987
)
The neurogenic gene Delta of Drosophila melanogaster is expressed in neurogenic territories and encodes a putative transmembrane protein with EGF-like repeats.
EMBO J
6
,
3431
3440
Weinmaster
G.
,
Roberts
V. J.
,
Lemke
G.
(
1991
)
A homolog of Drosophila Notch expressed during mammalian development.
Development
113
,
199
205
Weinmaster
G.
,
Roberts
V. J.
,
Lemke
G.
(
1992
)
Notch2: a second mammalian Notch gene.
Development
116
,
931
941
Wharton
K. A.
,
Johansen
K. M.
,
Xu
T.
,
Artavanis Tsakonas
S.
(
1985
)
Nucleotide sequence from the neurogenic locus Notch implies a geneproduct that shares homology with proteins containing EGF-like repeats.
Cell
43
,
567
581
Yamada
T.
,
Pfaff
S. L.
,
Edlund
T.
,
Jessell
T. M.
(
1993
)
Control of cellpattern in the neural-tube-motor-neuron induction by diffusible factors from notochord and floor plate.
Cell
73
,
673
686
Yamada
T.
,
Placzek
M.
,
Tanaka
H.
,
Dodd
J.
,
Jessell
T. M.
(
1991
)
Control of cell pattern in the developing nervous system: polarizing activity of the floor plate and notochord.
Cell
64
,
635
647
This content is only available via PDF.