The Notch signalling pathway plays essential roles during the specification of the rostral and caudal somite halves and subsequent segmentation of the paraxial mesoderm. We have re-investigated the role of presenilin 1 (Ps1; encoded by Psen1) during segmentation using newly generated alleles of the Psen1 mutation. In Psen1-deficient mice, proteolytic activation of Notch1 was significantly affected and the expression of several genes involved in the Notch signalling pathway was altered, including Δ-like3, Hes5, lunatic fringe (Lfng) and Mesp2. Thus, Ps1-dependent activation of the Notch pathway is essential for caudal half somite development. We observed defects in Notch signalling in both the caudal and rostral region of the presomitic mesoderm. In the caudal presomitic mesoderm, Ps1 was involved in maintaining the amplitude of cyclic activation of the Notch pathway, as represented by significant reduction of Lfng expression in Psen1-deficient mice. In the rostral presomitic mesoderm, rapid downregulation of the Mesp2 expression in the presumptive caudal half somite depends on Ps1 and is a prerequisite for caudal somite half specification. Chimaera analysis between Psen1-deficient and wild-type cells revealed that condensation of the wild-type cells in the caudal half somite was concordant with the formation of segment boundaries, while mutant and wild-type cells intermingled in the presomitic mesoderm. This implies that periodic activation of the Notch pathway in the presomitic mesoderm is still latent to segregate the presumptive rostral and caudal somite. A transient episode of Mesp2 expression might be needed for Notch activation by Ps1 to confer rostral or caudal properties. In summary, we propose that Ps1 is involved in the functional manifestation of the segmentation clock in the presomitic mesoderm.

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
Aoyama
H.
,
Asamoto
K.
(
1988
)
Determination of somite cells: independence of cell differentiation and morphogenesis.
Development
104
,
15
28
Aulehla
A.
,
Johnson
R. L.
(
1999
)
Dynamic expression of lunatic fringe suggests a link between notch signaling and an autonomous cellular oscillator driving somite segmentation.
Dev. Biol
207
,
49
61
Barrantes
I. B.
,
Elia
A. J.
,
Wunsch
K.
,
De Angelis
M. H.
,
Mak
T. W.
,
Rossant
J.
,
Conlon
R. A.
,
Gossler
A.
,
de la Pompa
J. L.
(
1999
)
Interaction between Notch signalling and Lunatic fringe during somite boundary formation in the mouse.
Curr. Biol
9
,
470
480
Bettenhausen
B.
,
HrabedeAngelis
M.
,
Simon
D.
,
Guenet
J. L.
,
Gossler
A.
(
1995
)
Transient and restricted expression during mouse embryogenesis of Dll1, a murine gene closely related to Drosophila Delta.
Development
121
,
2407
2418
Bruckner
K.
,
Perez
L.
,
Clausen
H.
,
Cohen
S.
(
2000
)
Glycosyltransferase activity of Fringe modulates Notch-Delta interactions.
Nature
406
,
411
415
Burgess
R.
,
Cserjesi
P.
,
Ligon
K. L.
,
Olson
E. N.
(
1995
)
Paraxis: a basic helix-loop-helix protein expressed in paraxial mesoderm and developing somites.
Dev. Biol
168
,
296
306
Cohen
B.
,
Bashirullah
A.
,
Dagnino
L.
,
Campbell
C.
,
Fisher
W. W.
,
Leow
C. C.
,
Whiting
E.
,
Ryan
D.
,
Zinyk
D.
,
Boulianne
G.
,
Hui
C. C.
, et al. 
(
1997
)
Fringe boundaries coincide with Notch-dependent patterning centres in mammals and alter Notch-dependent development in Drosophila.
Nat. Genet
16
,
283
288
Conlon
R. A.
,
Reaume
A. G.
,
Rossant
J.
(
1995
)
Notch1 is requiredfor the coordinate segmentation of somites.
Development
121
,
1533
1545
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
De Strooper
B.
,
Saftig
P.
,
Craessaerts
K.
,
Vanderstichele
H.
,
Guhde
G.
,
Annaert
W.
,
Von Figura
K.
,
Van Leuven
F.
(
1998
)
Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein.
Nature
391
,
387
390
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.
, et al. 
(
1999
)
A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain.
Nature
398
,
518
522
Donoviel
D. B.
,
Hadjantonakis
A. K.
,
Ikeda
M.
,
Zheng
H.
,
Hyslop
P. S.
,
Bernstein
A.
(
1999
)
Mice lacking both presenilin genes exhibit early embryonic patterning defects.
Genes Dev
13
,
2801
2810
Dunwoodie
S. L.
,
Henrique
D.
,
Harrison
S. M.
,
Beddington
R. S.
(
1997
)
Mouse Dll3: a novel divergent Delta gene which may complement the function of other Delta homologues during early pattern formation in the mouse embryo.
Development
124
,
3065
3076
Evrard
Y. A.
,
Lun
Y.
,
Aulehla
A.
,
Gan
L.
,
Johnson
R. L.
(
1998
)
lunatic fringe is an essential mediator of somite segmentation and patterning.
Nature
394
,
377
381
Goldstein
R. S.
,
Kalcheim
C.
(
1991
)
Normal segmentation and size of the primary sympathetic ganglia depend upon the alternation of rostrocaudal properties of the somites.
Development
112
,
327
334
Herreman
A.
,
Hartmann
D.
,
Annaert
W.
,
Saftig
P.
,
Craessaerts
K.
,
Serneels
L.
,
Umans
L.
,
Schrijvers
V.
,
Checler
F.
,
Vanderstichele
H.
, et al. 
(
1999
)
Presenilin 2 deficiency causes a mild pulmonary phenotype and no changes in amyloid precursor protein processing but enhances the embryonic lethal phenotype of presenilin 1 deficiency.
Proc. Natl. Acad. Sci. USA
96
,
11872
11877
Hrabe de Angelis
M.
,
McIntyre
J.
II
,
Gossler
A.
(
1997
)
Maintenanceof somite borders in mice requires the Delta homologue DII1.
Nature
386
,
717
721
Irvine
K. D.
(
1999
)
Fringe, Notch, and making developmental boundaries.
Curr. Opin. Genet. Dev
9
,
434
441
Jouve
C.
,
Palmeirim
I.
,
Henrique
D.
,
Beckers
J.
,
Gossler
A.
,
Ish-Horowicz
D.
,
Pourquie
O.
(
2000
)
Notch signalling is required for cyclic expression of the hairy-like gene HES1 in the presomitic mesoderm.
Development
127
,
1421
1429
Kessel
M.
,
Gruss
P.
(
1991
)
Homeotic transformations of murine vertebrae and concomitant alteration of Hox codes induced by retinoic acid.
Cell
67
,
89
104
Kusumi
K.
,
Sun
E. S.
,
Kerrebrock
A. W.
,
Bronson
R. T.
,
Chi
D. C.
,
Bulotsky
M. S.
,
Spencer
J. B.
,
Birren
B. W.
,
Frankel
W. N.
,
Lander
E. S.
(
1998
)
The mouse pudgy mutation disrupts Delta homologue Dll3 and initiation of early somite boundaries.
Nat. Genet
19
,
274
278
Levitan
D.
,
Doyle
T. G.
,
Brousseau
D.
,
Lee
M. K.
,
Thinakaran
G.
,
Slunt
H. H.
,
Sisodia
S. S.
,
Greenwald
I.
(
1996
)
Assessment of normal and mutant human presenilin function in Caenorhabditis elegans.
Proc. Natl. Acad. Sci. USA
93
,
14940
14944
Mansouri
A.
,
Yokota
Y.
,
Wehr
R.
,
Copeland
N. G.
,
Jenkins
N. A.
,
Gruss
P.
(
1997
)
Paired-related murine homeobox gene expressed in the developing sclerotome, kidney, and nervous system.
Dev. Dyn
210
,
53
65
Maynard
T. M.
,
Wakamatsu
Y.
,
Weston
J. A.
(
2000
)
Cell interactions within nascent neural crest cell populations transiently promote death of neurogenic precursors.
Development
127
,
4561
4572
McGrew
M. J.
,
Dale
J. K.
,
Fraboulet
S.
,
Pourquie
O.
(
1998
)
The lunatic fringe gene is a target of the molecular clock linked to somite segmentation in avian embryos.
Curr Biol
8
,
979
982
Moloney
D. J.
,
Panin
V. M.
,
Johnston
S. H.
,
Chen
J.
,
Shao
L.
,
Wilson
R.
,
Wang
Y.
,
Stanley
P.
,
Irvine
K. D.
,
Haltiwanger
R. S.
,
Vogt
T. F.
(
2000
)
Fringe is a glycosyltransferase that modifies Notch.
Nature
406
,
369
375
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
Nishimura
M.
,
Isaka
F.
,
Ishibashi
M.
,
Tomita
K.
,
Tsuda
H.
,
Nakanishi
S.
,
Kageyama
R.
(
1998
)
Structure, chromosomal locus, and promoter of mouse Hes2 gene, a homologue of Drosophila hairy and Enhancer of split.
Genomics
49
,
69
75
Palmeirim
I.
,
Henrique
D.
,
Ish-Horowicz
D.
,
Pourquie
O.
(
1997
)
Avian hairy gene expression identifies a molecular clock linked to vertebrate segmentation and somitogenesis.
Cell
91
,
639
648
Panin
V. M.
,
Papayannopoulos
V.
,
Wilson
R.
,
Irvine
K. D.
(
1997
)
Fringe modulates Notch-ligand interactions.
Nature
387
,
908
912
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
Rovescalli
A. C.
,
Asoh
S.
,
Nirenberg
M.
(
1996
)
Cloning and characterization of four murine homeobox genes.
Proc. Natl. Acad. Sci. USA
93
,
10691
10696
Saga
Y.
,
Hata
N.
,
Koseki
H.
,
Taketo
M. M.
(
1997
)
Mesp2: a novel mouse gene expressed in the presegmented mesoderm and essential for segmentation initiation.
Genes Dev
11
,
1827
1839
Shen
J.
,
Bronson
R. T.
,
Chen
D. F.
,
Xia
W.
,
Selkoe
D. J.
,
Tonegawa
S.
(
1997
)
Skeletal and CNS defects in Presenilin-1-deficient mice.
Cell
89
,
629
639
Sherrington
R.
,
Rogaev
E. I.
,
Liang
Y.
,
Rogaeva
E. A.
,
Levesque
G.
,
Ikeda
M.
,
Chi
H.
,
Lin
C.
,
Li
G.
,
Holman
K.
, et al. 
. (
1995
)
Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease.
Nature
375
,
754
760
Sosic
D.
,
Brand-Saberi
B.
,
Schmidt
C.
,
Christ
B.
,
Olson
E. N.
(
1997
)
Regulation of paraxis expression and somite formation by ectoderm-and neural tube-derived signals.
Dev. Biol
185
,
229
243
Stern
C. D.
,
Keynes
R. J.
(
1987
)
Interactions between somite cells: the formation and maintenance of segment boundaries in the chick embryo.
Development
99
,
261
272
Struhl
G.
,
Greenwald
I.
(
1999
)
Presenilin is required for activity and nuclear access of Notch in Drosophila.
Nature
398
,
522
525
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
Takahashi
Y.
,
Koizumi
K.
,
Takagi
A.
,
Kitajima
S.
,
Inoue
T.
,
Koseki
H.
,
Saga
Y.
(
2000
)
Mesp2 initiates somite segmentation through the Notch signalling pathway.
Nat. Genet
25
,
390
396
Wakamatsu
Y.
,
Maynard
T. M.
,
Weston
J. A.
(
2000
)
Fate determination of neural crest cells by NOTCH-mediated lateral inhibition and asymmetrical cell division during gangliogenesis.
Development
127
,
2811
2821
Wallin
J.
,
Wilting
J.
,
Koseki
H.
,
Fritsch
R.
,
Christ
B.
,
Balling
R.
(
1994
)
The role of Pax-1 in axial skeleton development.
Development
120
,
1109
1121
Weinmaster
G.
,
Roberts
V. J.
,
Lemke
G.
(
1992
)
Notch2: a second mammalian Notch gene.
Development
116
,
931
941
Wolfe
M. S.
,
Xia
W.
,
Ostaszewski
B. L.
,
Diehl
T. S.
,
Kimberly
W. T.
,
Selkoe
D. J.
(
1999
)
Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity.
Nature
398
,
513
517
Wong
P. C.
,
Zheng
H.
,
Chen
H.
,
Becher
M. W.
,
Sirinathsinghji
D. J.
,
Trumbauer
M. E.
,
Chen
H. Y.
,
Price
D. L.
,
Van der Ploeg
L. H.
,
Sisodia
S. S.
(
1997
)
Presenilin 1 is required for Notch1 and DII1 expression in the paraxial mesoderm.
Nature
387
,
288
292
Yagi
T.
,
Nada
S.
,
Watanabe
N.
,
Tamemoto
H.
,
Kohmura
N.
,
Ikawa
Y.
,
Aizawa
S.
(
1993
)
A novel negative selection for homologous recombinants using diphtheria toxin A fragment gene.
Anal. Biochem
214
,
77
86
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
Ye
Y.
,
Lukinova
N.
,
Fortini
M. E.
(
1999
)
Neurogenic phenotypes and altered Notch processing in Drosophila Presenilin mutants.
Nature
398
,
525
529
Zambrowicz
B. P.
,
Imamoto
A.
,
Fiering
S.
,
Herzenberg
L. A.
,
Kerr
W. G.
,
Soriano
P.
(
1997
)
Disruption of overlapping transcripts in the ROSA beta geo 26 gene trap strain leads to widespread expression of beta-galactosidase in mouse embryos and hematopoietic cells.
Proc. Natl. Acad. Sci. USA
94
,
3789
3794
Zhang
N.
,
Gridley
T.
(
1998
)
Defects in somite formation in lunatic fringe deficient mice.
Nature
394
,
374
377
This content is only available via PDF.