The Notch (N) pathway defines an evolutionarily conserved cell signaling mechanism that governs cell fate choices through local cell interactions. The ankyrin repeat region of the Notch receptor is essential for signaling and has been implicated in the interactions between Notch and two intracellular elements of the pathway: Deltex (Dx) and Suppressor of Hairless (Su(H)). Here we examine directly the function of the Notch cdc10/ankyrin repeats (ANK repeats) by transgenic and biochemical analysis. We present evidence implicating the ANK repeats in the regulation of Notch signaling through homotypic interactions. In vivo expression of the Notch ANK repeats reveals a cell non-autonomous effect and elicits mutant phenotypes that indicate the existence of novel downstream events in Notch signaling. These signaling activities are independent of the known effector Su(H) and suggest the existence of yet unidentified Notch pathway components.

REFERENCES

Artavanis-Tsakonas
S.
,
Matsuno
K.
,
Fortini
M. E.
(
1995
)
Notch signaling.
Science
268
,
225
232
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
Baker
N.E.
,
Yu
S.
,
Han
D.
(
1996
)
Evolution of proneural atonal expression during distinct regulatory phases in the developing Drosophila eye.
Curr. Biol
6
,
1290
301
Bang
A.G.
,
Posakony
J.W.
(
1992
)
The Drosophila gene Hairless encodes a novel basic protein that controls alternative cell fates in adult sensory organ development.
Genes Dev
6
,
1752
1769
Cagan
R.L.
,
Ready
D.F.
(
1989
)
Notch is required for successive cell decisions in the developing Drosophila retina.
Genes Dev
3
,
1099
1112
Diederich
R.J.
,
Matsuno
K.
,
Hing
H.
,
Artavanis-Tsakonas
S.
(
1994
)
Cytosolic interaction between deltex and Notch ankyrin repeats implicates deltex in the Notch signaling pathway.
Development
120
,
473
481
Eastman
D.S.
,
Slee
R.
,
Skoufos
E.
,
Bangalore
L.
,
Bray
S.
,
Delidakis
C.
(
1997
)
Synergy between Suppressor of Hairless and Notch in regulation of Enhancer of split mand m expression.
Mol. Cell Biol
17
,
5620
5628
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
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
Fortini
M.E.
,
Artavanis-Tsakonas
S.
(
1994
)
The Suppressor of Hairless protein participates in Notch receptor signaling.
Cell
79
,
273
282
Hubbard
A.
,
Dong
Q.
,
Greenwald
I.
(
1996
)
Evidence for physical and functional association between EMB-5 and LIN-12 in Caenorhabditis elegans.
Science
273
,
112
115
Jarriault
S.
,
Brou
C.
,
Logeat
F.
,
Schroeter
E.H.
,
Kopan
R.
,
Israel
A.
(
1995
)
Signalling downstream of activated mammalian Notch.
Nature
377
,
355
358
Jennings
B.
,
Preiss
A.
,
Delidakis
C.
,
Bray
S.
(
1994
)
The Notch signaling pathway is required for Enhancer of split bHLH protein expression during neurogenesis in the Drosophila embryo.
Development
120
,
3537
3548
Kidd
S.
(
1992
)
Characterization of the Drosophilacactus locus and analysis of interactions between cactus and dorsal proteins.
Cell
71
,
623
635
Kopczynski
C. C.
,
Alton
A. K.
,
Fechtel
K.
,
Kooh
P.H.
,
Muskavitch
M.A.
(
1988
)
Delta, a Drosophila neurogenic gene, is transcriptionallycomplex and encodes a protein related to blood coagulation factors and epidermal growth factors of vertebrates.
Genes Dev
2
,
1723
1735
Lecourtois
M.
,
Schweisguth
F.
(
1995
)
The neurogenic Suppressor 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
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
Matsuno
K.
,
Diederich
R.J.
,
Go
M.J.
,
Blaumueller
C. M.
,
Artavanis-Tsakonas
S.
(
1995
)
Deltex acts as a positive regulator of Notch signaling through interactions with the Notch ankyrin repeats.
Development
121
,
2633
2644
Rebay
I.
,
Fehon
R.
,
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 of ankyrin repeats.
Nature
364
,
632
635
Roehl
H.
,
Bosenberg
M.
,
Blelloch
R.
,
Kimble
J.
(
1996
)
Roles of the RAM and ANK domains in signaling by C. elegans GLP-1 receptor.
EMBO J
15
,
7002
7012
Rubin
G. M.
,
Spradling
A.C.
(
1982
)
Genetic transformation of Drosophila with transposable element vectors.
Science
218
,
348
353
Shawber
C.
,
Nofziger
D.
,
Hsieh
J.J.-D.
,
Lindsell
C.
,
Bogler
O.
,
Hayward
D.
,
Weinmaster
G.
(
1996
)
Notch Signaling inhibits muscle cell differentiation through a CBF1-independent pathway.
Development
122
,
3765
3773
Stifani
S.
,
Blaumueller
C.M.
,
Redhead
N. J.
,
Hill
R. E.
,
Artavanis-Tsakonas
S.
(
1992
)
Human homologs of a DrosophilaEnhancer of split gene product define a novel family of nuclear proteins.
Nature Genetics
2
,
119
127
Struhl
G.
,
Fitzgerald
K.
,
Greenwald
I.
(
1993
)
Intrinsic activity of the LIN-12 and Notch intracellular domains in vivo.
Cell
74
,
331
345
Sun
X.
,
Artavanis-Tsakonas
S.
(
1996
)
The intracellular deletions of DELTA and SERRATE define dominant negative forms of the Drosophila Notch ligands.
Development
122
,
2465
2474
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).
Current Biology
5
,
1416
1423
Tamura
K.
,
Taniguchi
Y.
,
Minoguchim
S.
,
Sakai
T.
,
Tin
T.
,
Furukawa
T.
,
Honjo
T.
(
1995
)
Physical interaction of a novel domain of the notch receptor with the RBP-Jk transcription factor.
Curr. Biol
5
,
1416
1423
Verheyen
E. M.
,
Purcell
K. J.
,
Fortini
M. E.
,
Artavanis-Tsakonas
S.
(
1996
)
Analysis of dominant enhancers and suppressors of activated Notch in Drosophila.
Genetics
144
,
1127
1141
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
Wilkinson
H.
,
Fizgerald
K.
,
Greenwald.
I.
(
1994
)
Reciprocal changes in expression of the receptor lin-12 and its ligand lag-2 prior to commitment in a C. elegans cell fate decision.
Cell
79
,
1187
1198
Xu
T.
,
Rebay
I.
,
Fleming
R. J.
,
Scottgale
T. N.
,
Artavanis-Tsakonas
S.
(
1990
)
The Notch locus and the genetic circuitry involved in early Drosophila neurogenesis.
GenesDev
4
,
464
475
Zervos
A.S.
,
Gyuris
J.
,
Brent
R.
(
1993
)
Mxi1, a protein that specifically interacts with Max to bind Myc-Max recognition sites.
Cell
72
,
223
232
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