The Notch signaling pathway is important for cellular differentiation. The current view is that the Notch receptor is cleaved intracellularly upon ligand activation. The intracellular Notch domain then translocates to the nucleus, binds to Suppressor of Hairless (RBP-Jk in mammals), and acts as a transactivator of Enhancer of Split (HES in mammals) gene expression. In this report we show that the Notch 3 intracellular domain (IC), in contrast to all other analysed Notch ICs, is a poor activator, and in fact acts as a repressor by blocking the ability of the Notch 1 IC to activate expression through the HES-1 and HES-5 promoters. We present a model in which Notch 3 IC interferes with Notch 1 IC-mediated activation at two levels. First, Notch 3 IC competes with Notch 1 IC for access to RBP-Jk and does not activate transcription when positioned close to a promoter. Second, Notch 3 IC appears to compete with Notch 1 IC for a common coactivator present in limiting amounts. In conclusion, this is the first example of a Notch IC that functions as a repressor in Enhancer of Split/HES upregulation, and shows that mammalian Notch receptors have acquired distinct functions during evolution.

Reference

Akazawa
C.
,
Sasai
Y.
,
Nakanishi
S.
,
Kageyama
R.
(
1992
)
Molecular characterization of a rat negative regulator with a basic helix-loop-helix structure predominantly expressed in the developing nervous system.
J. Biol. Chem
267
,
21879
21885
Bailey
A. M.
,
Posakony
J. W.
(
1995
)
Suppressor of hairless directly activates transcription of Enhancer of split complex genes in response to Notch receptor activity.
Genes Dev
9
,
2609
2622
Beatus
P.
,
Lendahl
U.
(
1998
)
Notch and neurogenesis.
J. Neurosci. Res
54
,
125
136
Chitnis
A.
,
Henrique
D.
,
Lewis
J.
,
Ish-Horowicz
D.
,
Kintner
C.
(
1995
)
Primary neurogenesis in Xenopus embryos regulated by a homologue of the Drosophila neurogenic gene Delta.
Nature
375
,
761
766
Chung
C.-N.
,
Hamaguchi
Y.
,
Honjo
T.
,
Kawaichi
M.
(
1994
)
Site-directed mutagenesis study on DNA binding regions of the mouse homologue of Suppressor of Hairless, RBP-Jk.
Nucl. Acids Res
22
,
2938
2944
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
)
Notch 1 is required for the coordinate segmentation of somites.
Development
121
,
1533
1545
de la Pompa
J. L.
,
Wakeham
A.
,
Correia
K. M.
,
Samper
E.
,
Brown
S.
,
Aguilera
R. J.
,
Nakano
T.
,
Honjo
T.
,
Mak
T. W.
,
Rossant
J.
,
Conlon
R. A.
(
1997
)
Conservation of the Notch signalling pathway in mammalian neurogenesis.
Development
124
,
1139
1148
De Strooper
B.
,
Annaert
W.
,
Cupers
P.
,
Saftig
P.
,
Craessaerts
K.
,
Mumm
J.S.
,
Schroeter
E.H.
,
Schrijvers
V.
,
Wolfe
M.S.
,
Ray
W.J.
,
Goate
A.
,
Kopan
R.
(
1999
)
A presenilin-1-dependent-secretase-like protease mediates release of Notch intracellular domain.
Nature
398
,
518
521
Dorsky
R. I.
,
Rapaport
D. H.
,
Harris
W. A.
(
1995
)
Xotch inhibits cell differentiation in the Xenopus retina.
Neuron
14
,
487
496
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 DrosophilaNotch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms.
Cell
66
,
649
661
Fitzgerald
K.
,
Wilkinson
H. A.
,
Greenwald
I.
(
1993
)
glp-1 can substitute for lin-12 in specifying cell fate decisions in Caenorhabditis elegans.
Development
119
,
1019
1027
Fortini
M. E.
,
Artavanis-Tsakonas
S.
(
1994
)
The Suppressor of Hairless protein participates in Notch receptor signaling.
Cell
79
,
273
282
Fortini
M. E.
,
Rebay
I.
,
Caron
L. A.
,
Artavanis-Tsakonas
S.
(
1993
)
An activated Notch receptor blocks cell-fate commitment in the developing Drosophila eye.
Nature
365
,
555
557
Furukawa
T.
,
Kobayakawa
Y.
,
Tamura
K.
,
Kimura
K. i.
,
Kawaichi
M.
,
Tanimura
T.
,
Honjo
T.
(
1995
)
Suppressor of Hairless, the Drosophila homologue of RBP-Jk, transactivates the neurogenic gene E(spl)m8.
Japan. J. Genet
70
,
505
524
Hsieh
J. J.-D.
,
Henkel
T.
,
Salmon
P.
,
Robey
E.
,
Peterson
M. G.
,
Hayward
S. D.
(
1996
)
Truncated mammalian Notch1 activates CBF1/RBP-Jk-repressed genes by a mechanism resembling that of Epstein-Barr virus EBNA2.
Mol. Cell Biol
16
,
952
959
Ishibashi
M.
,
Ang
S.-L.
,
Shiota
K.
,
Nakanishi
S.
,
Kageyama
R.
,
Guillemot
F.
(
1995
)
Targeted disruption of mammalian hairy and Enhancer of split homolog-1 (HES-1) leads to up-regulation of neural helix-loop-helix factors, premature neurogenesis, and severe neural tube defects.
Genes Dev
9
,
3136
3148
Jarriault
S.
,
Brou
C.
,
Logeat
F.
,
Schroeter
E. H.
,
Kopan
R.
,
Israel
A.
(
1995
)
Signalling downstream of activated mammalian Notch.
Nature
377
,
355
358
Joutel
A.
,
Corpechot
C.
,
Ducros
A.
,
Vahedi
K.
,
Chabriat
H.
,
Mouton
P.
,
Alamowitch
S.
,
Domenga
V.
,
Cecillion
M.
,
Marechal
E.
,
Maciazek
J.
,
Vayssiere
E.
,
Cruaud
C.
,
Cabanis
E.-A.
,
Ruchoux
M. M.
,
Weissenbach
J.
,
Bach
J. F.
,
Bousser
M. G.
,
Tournier-Lasserve
E.
(
1996
)
Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia.
Nature
383
,
707
710
Joutel
A.
,
Vahedi
K.
,
Corpechot
C.
,
Troesch
A.
,
Chabriat
H.
,
Vayssiere
C.
,
Cruaud
C.
,
Maciazek
J.
,
Weissenbach
J.
,
Bousser
M.-G.
,
Bach
J.-F.
,
Tournier-Lasserve
E.
(
1997
)
Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients.
Lancet
350
,
1511
1515
Kang
T.
,
Martins
T.
,
Sadowski
I.
(
1993
)
Wild-typeGAL4 binds cooperatively to the GAL1-10 UASg in vitro.
J Biol.Chem
268
,
9629
9635
Kato
H.
,
Sakai
T.
,
Tamura
K.
,
Minoguchi
S.
,
shirayoshi
Y.
,
Hamada
Y.
,
Tsujimoto
Y.
,
Honjo
T.
(
1996
)
Functional conservation of mouse Notch receptor family members.
FEBS Lett
395
,
221
224
Kato
H.
,
Taniguchi
Y.
,
Kurooka
H.
,
Minoguchi
S.
,
Sakai
T.
,
Nomura-Okazaki
S.
,
Tamura
K.
,
Honjo
T.
(
1997
)
Involvement of RBP-J in biological functions of mouse Notch1 and its derivatives.
Development
124
,
4133
4141
Kidd
S.
,
Kelley
M. R.
,
Young
M. W.
(
1986
)
Sequence of the Notch locus of Drosophila melanogaster: Relationship of the encoded protein to mammalian clotting and growth factors.
Mol. Cell. Biol
6
,
3094
3108
Kopan
R.
,
Schroeter
E. H.
,
Weintraub
H.
,
Nye
J. S.
(
1996
)
Signal transduction by activated mNotch: importance of proteolytic processing and its regulation by the extracellular domain.
Proc. Natl. Acad. Sci. USA
93
,
1683
1688
Lardelli
M.
,
Dahlstrand
J.
,
Lendahl
U.
(
1994
)
The novel Notch homologue mouse Notch3 lacks specific EGF-repeats and is expressed in proliferating neuroepithelium.
Mech. Dev
46
,
123
136
Lardelli
M.
,
Williams
R.
,
Mitsiadis
T.
,
Lendahl
U.
(
1996
)
Expression of the Notch 3 intracellular domain in mouse central nervous system progenitor cells is lethal and leads to disturbed neural tube development.
Mech. Dev
59
,
177
190
Lecourtois
M.
,
Schweisguth
F.
(
1995
)
The neurogenic Supressor of Hairless DNA-binding protein mediates the transcriptional activation of the Enhancer of split complex genes triggered by Notch signaling.
Genes Dev
9
,
2598
2608
Lewis
J.
(
1996
)
Neurogenic genes and vertebrate neurogenesis.
Curr. Opin. Neurobiol
6
,
3
10
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
Lindsell
C. E.
,
Boutler
J.
,
diSibio
G.
,
Gossler
A.
,
Weinmaster
G.
(
1996
)
Expression patterns of Jagged, Delta1, Notch1, Notch2 and Notch3 genes identify ligand-receptor pairs that may function in neural development.
Mol. Cell. Neurosci
8
,
14
27
Mitsiadis
T. A.
,
Henrique
D.
,
Thesleff
I.
,
Lendahl
U.
(
1997
)
Mouse Serrate-1 (Jagged-1): expression in the developing tooth is regulated by epithelial-mesenchymal interactions and fibroblast growth factor-4.
Development
124
,
1473
1483
Nye
J. S.
,
Kopan
R.
,
Axel
R.
(
1994
)
An activated Notch suppresses neurogenesis and myogenesis but not gliogenesis in mammalian cells.
Development
120
,
2421
2430
Perlmann
T.
,
Jansson
L.
(
1995
)
A novel pathway for vitamin A signaling mediated by RXR heterodimerization with NGFI-B and NURR1.
Genes Dev
9
,
769
782
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
Schroeter
E. H.
,
Kisslinger
J. A.
,
Kopan
R.
(
1998
)
Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain.
Nature
393
,
382
385
Simpson
P.
(
1997
)
Notch signalling in development: on equivalence groups and asymmetric developmental potential.
Curr. Opin. Gen. Dev
7
,
537
542
Struhl
G.
,
Adachi
A.
(
1998
)
Nuclear access and action of Notch in vivo.
Cell
93
,
649
660
Struhl
G.
,
Fitzgerald
K.
,
Greenwald
I.
(
1993
)
Intrinsic activity of the lin-12 and Notch intracellular domains in vivo.
Cell
74
,
331
345
Struhl
G.
,
Greenwald
I.
(
1999
)
Presenilin is required for activity and nuclear access of Notch in Drosophila.
Nature
398
,
522
524
Swiatek
P. J.
,
Lindsell
C. E.
,
Franco del Amo
F.
,
Weinmaster
G.
,
Gridley
T.
(
1994
)
Notch 1 is essential for postimplantation development in mice.
Genes Dev
8
,
707
719
Tamura
K.
,
Taniguchi
Y.
,
Minoguchi
S.
,
Sakai
T.
,
Tun
T.
,
Furukawa
T.
,
Honjo
T.
(
1995
)
Physical interaction between a novel domain of the receptor Notch and the transcription factor RBP-Jk/Su(H).
Curr. Biol
5
,
1416
1423
Weinmaster
G.
(
1997
)
The Ins and Outs of Notch signaling.
Mol. Cell. Neurosci
9
,
91
102
Wettstein
D. A.
,
Turner
D. L.
,
Kintner
C.
(
1997
)
The Xenopus homolog of Drosophila Suppressor of Hairless mediates Notch signaling during primary neurogenesis.
Development
124
,
693
702
Wharton
K. A.
,
Johansen
K. M.
,
Xu
T.
,
Artavanis-Tsakonas
S.
(
1985
)
Nucleotide sequence from the neurogenic locus Notch implies a gene product that shares homology with proteins containing EGF-like repeats.
Cell
43
,
567
581
This content is only available via PDF.