Members of the Notch family of transmembrane receptors mediate a number of developmental decisions in invertebrates. In order to study Notch function in a vertebrate organism, we have mutated the Notch1 gene of the mouse. Notch1 gene function is required for embryonic survival in the second half of gestation. In the first half of gestation, we have found no effect of the mutation on the normal programs of neurogenesis, myogenesis or apoptosis. We conclude that Notch1 function is not essential for these processes, at least in early postimplantation development. However, we have found that somitogenesis is delayed and disorganized in Notch1 mutant embryos. We propose that Notch1 normally coordinates the process of somitogenesis, and we provide a model of how this might occur.

Reference

Cagan
R. L.
,
Ready
D. F.
(
1989
)
Notch is required for successive cell decisions in the developing Drosophila retina.
Genes Dev
3
,
1099
1112
Candia
A. F.
,
Hu
H.
,
Crosby
J.
,
Lalley
P. A.
,
Noden
D.
,
Nadeau
J. H.
,
Wright
C. V. E.
(
1992
)
Mox-1 and Mox-2 define a novel homeobox gene subfamily and are differentially expressed during early mesodermal patterning in mouse embryos.
Development
116
,
1123
1136
Chesley
P.
(
1935
)
Development of the short-tailed mutant in the house mouse.
J. Exp. Zool
70
,
429
435
Coffman
C.
,
Harris
W.
,
Kintner
C. R.
(
1990
)
Xotch, the Xenopus homolog of Drosophila Notch.
Science
249
,
1438
1441
Conlon
R. A.
,
Rossant
J.
(
1992
)
Exogenous retinoic acid rapidly induces anterior ectopic expression of murine Hox-2 genes in vivo.
Development
116
,
357
368
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
Davis
C. A.
,
Holmyard
D. P.
,
Millen
K. J.
,
Joyner
A. L.
(
1991
)
Examining pattern formation in mouse, chicken and frog embryos with an En -specific antiserum.
Development
111
,
287
298
Deng
C.-X.
,
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
Dunn
L. C.
,
Gluecksohn-Schoenheimer
S.
,
Bryson
V.
(
1940
)
A new mutation in the mouse affecting spinal column and urogenital system.
J. Hered
31
,
343
348
Echelard
Y.
,
Epstein
D. J.
,
St-Jacques
B.
,
Shen
L.
,
Mohler
J.
,
McMahon
J. A.
,
McMahon
A. P.
(
1993
)
Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity.
Cell
75
,
1417
1430
Ellisen
L. W.
,
Bird
J.
,
West
D. C.
,
Soreng
A. L.
,
Reynolds
T. C.
,
Smith
S. D.
,
Sklar
J.
(
1991
)
Tan-1, the human homologue 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. T.
,
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
Fleming
R. J.
,
Scottgale
T. N.
,
Diederich
R. J.
,
Artavanis-Tsakonas
S.
(
1990
)
The gene Serrate encodes a putative EGF-like transmembrane protein essential for proper ectodermal development in Drosophila melanogaster.
Genes Dev
4
,
2188
2201
Fortini
M. E.
,
Artavanis-Tsakonas
S.
(
1994
)
The suppressor of hairless protein participates in Notch receptor signaling.
Cell
79
,
273
282
Franco del Amo
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
Gavrieli
Y.
,
Sherman
Y.
,
Ben-Sasson
S. A.
(
1992
)
Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation.
J. Cell Biol
119
,
493
501
Ghysen
A.
,
Dambly-Chaudiere
C.
,
Jan
L. Y.
,
Jan
Y.-N.
(
1993
)
Cellinteractions and gene interactions in peripheral neurogenesis.
Genes Dev
7
,
723
733
Graham
A.
,
Heyman
I.
,
Lumsden
A.
(
1993
)
Even-numbered rhombomeres control the apoptotic elimination of neural crest cells from odd-numbered rhombomeres in the chick hindbrain.
Development
119
,
233
245
Greenspan
R. J.
(
1990
)
The Notch gene, adhesion, and developmental fate in the Drosophila embryo.
New Biologist
2
,
595
600
Greenwald
I.
,
Rubin
G. M.
(
1992
)
Making a difference: the role of cell-cell interactions in establishing separate identities for equivalent cells.
Cell
68
,
271
281
Greenwald
I. S.
,
Sternberg
P. W.
,
Horvitz
H. R.
(
1983
)
The lin-12 locus specifies cell fates in Caenorhabditis elegans.
Cell
34
,
435
444
Guillemot
F.
,
Joyner
A. L.
(
1993
)
Dynamic expression of the murine achaete-scute homolog (MASH-1) in the developing nervous system.
Mech. Dev
42
,
171
185
Guillemot
F.
,
Lo
L.-C.
,
Johnson
J. E.
,
Auerbach
A.
,
Anderson
D. J.
,
Joyner
A. L.
(
1993
)
Mammalian achaete-scute homolog 1 is required for the early development of olfactory and autonomic neurons.
Cell
75
,
463
476
Hartenstein
V.
,
Posakony
J. W.
(
1990
)
A dual function of the Notch gene in Drosophila sensillum development.
Dev. Biol
142
,
13
30
Hartenstein
A. Y.
,
Rugendorff
A.
,
Tepass
U.
,
Hartenstein
V.
(
1992
)
The fuction of the neurogenic genes during epithelial development in the Drosophila embryo.
Development
116
,
1203
1220
Heitzler
P.
,
Simpson
P.
(
1991
)
The choice of cell fate in the epidermis of Drosophila.
Cell
64
,
1083
1092
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
Herrmann
B. G.
(
1991
)
Expression pattern of the Brachyury gene in whole-mount Twis / TWis mutant embryos.
Development
113
,
913
917
Jeffs
P.
,
Jaques
K.
,
Osmond
M.
(
1992
)
Cell death in cranial neural crest development.
Anat. Embryol
185
,
583
588
Jeffs
P.
,
Osmond
M.
(
1992
)
A segmented pattern of cell death during development of the chick embryo.
Anat. Embryol
185
,
589
598
Karnovsky
M. J.
(
1965
)
A formaldehyde-glutaraldehyde fixative of high osmolarity for use in electron microscopy.
J. Cell Biol
27
,
137
–.
Keynes
R. J.
,
Stern
C. D.
(
1988
)
Mechanisms of vertebrate segmentation.
Development
103
,
413
429
Kopan
R.
,
Nye
J. S.
,
Weintraub
H.
(
1994
)
The intracellular domain of mouse Notch: a constitutively activated repressor of myogenesis directed at the basic helix-loop-helix region of MyoD.
Development
120
,
2385
2396
Kosecki
H.
,
Wallin
J.
,
Wilting
J.
,
Mizutani
Y.
,
Kispert
A.
,
Ebensperger
C.
,
Herrmann
B.
,
Christ
B.
,
Balling
R.
(
1993
)
A role for Pax-1 as a mediator of notochordal signals during the dorsoventral specification of vertebrae.
Development
119
,
649
660
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
,
364
372
Lardelli
M.
,
Dahlstrand
J.
,
Lendahl
U.
(
1994
)
The novel Notch homologue mouse Notch 3 lacks specific EGF-repeats and is expressed in proliferating neuroepithelium.
Mech. Dev
46
,
123
136
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
Lieber
T.
,
Kidd
S.
,
Alcamo
E.
,
Corbin
V.
,
Young
M. W.
(
1993
)
Antineurogenic phenotypes induced by truncated Notch proteins indicate a role in signal transduction and may point to a novel function for Notch in nuclei.
Genes Dev
7
,
1949
1965
Mansour
S. L.
,
Thomas
K. R.
,
Capecchi
M. R.
(
1988
)
Disruption of the proto-oncogene int-2 in mouse embryo-derived stem cells: a general strategy for targeting mutations to non-selectable genes.
Nature
336
,
348
352
Meier
S.
(
1984
)
Somite formation and its relationship to metameric patterning of the mesoderm.
Cell Differentiation
14
,
235
243
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
Moens
C. B.
,
Auerbach
A. B.
,
Conlon
R. A.
,
Joyner
A. L.
,
Rossant
J.
(
1992
)
A targeted mutation reveals a role for N- myc in branching morphogenesis in the embryonic mouse lung.
Genes Dev
6
,
691
704
Nagy
A.
,
Rossant
J.
,
Nagy
R.
,
Abramow-Newerly
W.
,
Roder
J. C.
(
1993
)
Derivation of completely cell culture-derived mice from early-passage embryonic stem cells.
Proc. Natl. Acad. Sci. USA
90
,
8424
8428
Nye
J. S.
,
Kopan
R.
,
Axel
R.
(
1994
)
An activated Notch suppresses neurogenesis and myogenesis but not gliogenesis in mammalian cells.
Development
120
,
24521
2430
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.
,
Fehon
R. G.
,
Artavanis-Tsakonas
S.
(
1993
)
Specific truncations of Drosophila Notch define dominant activated and dominant negative forms of the receptor.
Cell
74
,
319
329
Roehl
H.
,
Kimble
J.
(
1993
)
Control of cell fate in C. elegans by a glp-1 peptide consisting primarily of ankyrin repeats.
Nature
364
,
642
635
Sternberg
P. W.
(
1988
)
Lateral inhibition during vulval induction in Caenorhabditis elegans.
Nature
335
,
551
554
Stifani
S.
,
Blaumueller
C. M.
,
Redhead
N. J.
,
Hill
R. E.
,
Artavanis-Tsakonas
S.
(
1992
)
Human homologs of a Drosophila Enhancer of Split gene product define a novel family of nuclear proteins.
Nature Genetics
2
,
119
126
Struhl
G.
,
Fitzgerald
K.
,
Greenwald
I.
(
1993
)
Intrinsic activity of the lin-12 and Notch intracellular domains in vivo.
Cell
74
,
331
345
Swiatek
P. J.
,
Lindsell
C. E.
,
del Amo
F. F.
,
Weinmaster
G.
,
Gridley
T.
(
1994
)
Notch1 is essential for postimplantation development in mice.
Genes Dev
8
,
707
719
Takada
S.
,
Stark
K. L.
,
Shea
M. J.
,
Vassileva
G.
,
McMahon
J. A.
,
McMahon
A. P.
(
1994
)
Wnt-3a regulates somite and tailbud formation in the mouse embryo.
Genes Dev
8
,
174
189
Tam
P. P. L.
,
Meier
S.
,
Jacobson
A. G.
(
1982
)
Differentiation of the metameric pattern in the embryonic axis of the mouse. II. Somitomeric organization of the presomitic mesoderm.
Differentiation
21
,
109
122
Tax
F. E.
,
Yeargers
J. J.
,
Thomas
J. H.
(
1994
)
Sequence of C. elegans lag-2 reveals a cell-signaling domain shared with Delta and Serrate of Drosophila.
Nature
368
,
150
154
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.
,
Lemke
G.
(
1991
)
A homolog of DrosophilaNotch 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
Wolf
C.
,
Thisse
C.
,
Stoetzel
C.
,
Thisse
B.
,
Gerlinger
P.
,
Perrin-Schmitt
F.
(
1991
)
The M-twist gene of Mus is expressed in subsets of mesodermal cells and is closely related to the Xenopus X-twi and the Drosophila twist genes.
Dev. Biol
143
,
363
373
Yamaguchi
T. P.
,
Conlon
R. A.
,
Rossant
J.
(
1992
)
Expression of the fibroblast growth factor receptor FGFR-1/flg during gastrulation and segmentation in the mouse embryo.
Dev. Biol
152
,
75
88
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
This content is only available via PDF.