- Email: [email protected]
Somitogenesis: segmenting a vertebrate
487
Somitogenesis:
segmenting
Michael J McGrew*
a vertebrate
and Olivier Pourquikt In man) \ crtcbfiltc species such ~1s the chick, :III~ zebrafish. somitcs form as cpithetial sphcrcs \\.hich l)ud off in a highI>- co-ordinated fashion from the \ crtcbrates.
The partitioning of the vertebrate body into a repetitive series of segments,
or somites,
~nouse
requires the spatially and temporally
co-ordinated behaviour of mesodermal cells. To date, it
rostra1
remains unknown how applicable our knowledge of the genetic mechanisms
governing Drosophila
be to that of vertebrates, though recent results degree of conservation.
Genetic studies
a major role for the Notch-Delta formation. the
Furthermore,
presomitic
indicate some
in the mouse point to
signalling pathway in somite
a molecular
clock
may
be ‘ticking’
in
Addresses Laboratolre de GBn6tlque et de Physlologie du D&eloppement (LGPD), Developmental Biology Institute of Marseille (IBDM), INSERM-UniversitB de la m8diterran&AP Lumlny, Case 907, 13288 Marseille Cedex
de Marseille, 09, France
de
C’ Current
in Genetics
Biology
I)iirin,<
& Development
Publications
ISSN
1998,
the this the ahI>
8:487-493
0959-437X
basic helix-loop-helix fibroblast growth factor
PSM
presomitic
contr;tst.
littlc
somitogcnesis
scgnicntul
clurin, (7 which
of the xrtcbratc
body
rcccntl~.
I:irst,
,q of ttic
the
1~~x1. In
about the proct‘ss
the basic sejinicnted Se\xxit
scgmentntion,
althou!:h
at the espcnsc the knock-oiit
se\,cral
of
pattern important
ho\\c\.rr. haIre major
patternin::
Soon terncd sues
2fter
their
to min,
the
of the lxiir-rule is discussed
system
obscr\ed
formation.
in rcsponsc [SlZ].
mesodcrni
[6]. hlore
of ‘Ifix
-
3 lxx+!
fxtor
-
ted to the app;lrcnt
ury-like
‘II
cpithcliat soniitcs
compartnicnt
I\ hich the x&II
in
here. \\~eIIISO discuss
sonlitcs
Ixconie
pat-
to loc~it signals from the surrounding
\cntrall!.
mescnch~inat
slxlcton
differcntiatc
called
Llriscs.
the
sclerotomc
and dorsalI>
tis-
into
into the dcr-
[.?.13,14].
cpithclial
On the basis of the differential
ious jicncs.
ncn4y formed cpithcti:il
to possess
anterior gi\ c rise
csprcssion
somitcs
of \;lr-
can bc consid-
and postcrioi- comp;irtments which to ;I \.isil)le ~intero-l~ostcrior (A[‘)
:i rcccntl\ idcntificd nioleciil:iiclock linked to \crtclmtc scgnicntation \\ hich pro\ ides molecular support for SC\ craI theoretical models of somitogencsis. I’urthcrmorc. SC\ cral targeted miitations in niicc ha\.c pro\ ided increasing c\ idcncc fol- 3 central rote of the KotcbI1clta signatlin,g lxith\\.a!, in the control of somitogcnesis.
sclcrotonic siilxii~.ision. ‘l’his siibclidsion wilt pro\,ide the Ixlsis for ;i law rt”scgnicntation proccs\ during diich the \ crtcbrac arc fornicd from the fusion of a caudal half soniitc n-ith the rostral half of the next soniite [1.5]. ‘I’hus. the jicncration and patterning of the soniites reclLiircs the integr;ition of niorphogenctic lxithwq3 with those go\ crnin,q cell fate. coml~~irtiiientali/ation . and tincqc slxcit~cation.
Origin and formation
Segmentation
/)mw~/Ii/~~
Somitcs th;it
;irc
scgmcnt:ltion
are transient prcscnt
in
of somites
scgmcnts dc\.clopiii::
of the pxixi:il
mcsodcrni
Sc~nicnt3tion
and
tic of ni:in\
CCl’h:ilochord;ltcs
3
from
and yields the hod) skctrtal ~~IISC~~S and prt of the dermis. It is beyond the scope of this rc\-ic\\ to discuss somitc lxittcrnin,g and the rcadcr i\ cncoiira,qed to conslilt the follo\ving rc~itxr’s
siitxccliicntt!
in son~itogcnesis
primiti\,e
nicsodcrm
momg otoiii6’ \\4iich rcixiins
cmbr\-0l;encsis
l)mrl,l’/‘i/0
allocated to
rostrat
rccruitcd
of paraxial
tr:lnscription
of p:ir;i\i:il
crcd
during
the
phenot>,pc uxs
nicnt
utitised
cells lxxomc
through
in de\~clopnicnt.
siirprisingl!.
becm to ha\ e been issue of \vhethcr 5ejinient:rtion :irosc indepcndentl~ in protostoimcs and dclitcl-ostonies rcniains ~1mittcr for spiritcd dcbatc. LSonic rcccnt olmm~ations offu siipport for the cxiswncc of ;I conscr\ cd nicch;inisiii: in particular. the possibtc in\ot\xs)5Wms
conscr\,eci from
of the
l)mwp~il~~
niolccular
is est:iblishcd.
issue’s rete\ Lint to \ crtebrate ;u-iscn
is known
numtxr.
into neur:it tissue [7”]. .A also reported for the txgcted niiitation of the secreted t:,ictor L\.nt-.3;i [Y]. ‘l’hese rcsutts suggcst that intricate si~n:illing p;ith\\x3 exist to direct ne\vl~ irlgrcssin,? cells to a pii-axial niesoderm fate.
Ixtttcrnin
\\xll understood ;It is Ic~iow~i moleciilarl~
nothing sornitc
in amniotes,
injircssion
nicsoderm
similar
mesoderm
of
i\ no\\’
\‘irtuatly
controlling
cells dcri\ze from tail bud. Sawit targctrd niousc mutations affecting prowss ha\c irecentl! l~cn idcntificct. For exanipte, niiit;ition of /~‘(~/~‘/?I ~rrsiitted in a toss of soniitcs, prob24 :in indirect co~ise~luxcc of the cllxinsion of axial later
con\,ersion receptor
Introduction Specification
after
I,()~-cont:liniri~
b-HLH FGFR
[S’].
fi;istrulation
I’Shl
\trcak;
Abbreviations AP antero-postenor
cnlt)r)o
species processes
the
Olivter Pourqul&
Opinion
I!- rel:itcd molccul;ir CNRS-
Campus
*e-mall: [email protected] .‘e-mall: [email protected]
Current
mal presoniitic niesoderni (I’Shl) [ 1.21. of these structures projircsses rostro-c;i1ictatt~ siiiiiiltaiicolist~ \vith the recruitnicnt of nt’\\’ nicscnch!m:il cells from the site of~astrulation into the caudal end of the I’SYI (I;igiire 1) [.3,-l]. .Soniitogencsis proceeds ;It ;I defined pee \\,hich is both teml’cratllrc-dcpcndent and species-specific. ‘I’he total niimbcr of somites is also . species-specitic and can Ix highly \.ariabte bctn ecn ctosc-
mesoderm.
Correspondence:
niesench)
‘I’hc generation
segmentation will
as a conserved mechanism
or metaineris3tion animal
spccics
is also ii basic characterisother
thin
the
\-errcbratcs.
488
Pattern formation and developmental
mechanisms
Figure 1
Figure 2
Rostra1
c
n
SI
Somite formation
Time Differentiation of somitic derivatives Somlte formatlon
(every 90 mins) c ”
Somites
Segment specification
@
‘P ; M
0 somites
4 somites Presomitic mesoderm
Chick somitogenesis Tail bud
17 somltes
Specification of paraxlal mesoderm fate
Caudal Current
Op~n~an in Genetics
Schematic representation of somite formatlon somlte 0; SI, somite I; SII, somite II.
,
& Development
from the PSM, SO,
Segmented thorax
13ody segmentation in these spwics usually corresponds to 2 rcpctition along the XI’ axis of similar strwtlircs consist-
ing of deribativcs from the three enihr)-onic gum layers. Serial segments are found in the annclid, insect, and \ c‘i-tcbrxc classes bur not in others - such as rhe molluscs and echinodcrn~s. As discussed above. segnient;ition in vcrtebratcs is most olxG)us in the trunk at the le\xl of rhe
Grasshopper segmentation
Fully segmented
\zrtcbral column, its associated muscles, and the pcriphcral nm 0~1ssystcni. Scgnicntation at rhe head Ia cl is found in the I,ranchial
archcs and the rhomlmneres
t,c discussed here. Somite inisccnt
of segmentation
formation
hut ~1ill not
is in many \v;lvs rem-
in short-germ
band insccrs
such
as the grasshopper. in w,hich scgnients arc added coiiscci~ti\xly from ;I rerminal groudi mnc (I:ijitirc 2) [lb]. ‘I’his mode of scgnientation
is in sharp contmt
to that found
Comparison segmentation
between somitogenesls in the chick embryo and In a short germ band insect, the grasshopper. In both
types of organisms,
In contrast
to Drosophila,
segments
are formed
after gastrulation and regularly appear In a rostra1 to caudal progression as the embryonic axls IS laid down. PS, primltlve TGZ, terminal growth zone.
streak;
in
all scgnicnrs are gcncratcd sinirllrancoiisly in a syncitial blastoderni [ 171. /)/v.iop/)/li/~, in uhich
not expressed sidcrrd
in segmenring
Ikcausc of this \‘ery particular niodc of scgnicntation, the transposition of the genetic hierarchy of the \vell-characterizcd /)msop~;/~ segmentation gents to the rest of the animal
pendently
kinjirloni
in contrast Cothe conser\2tion
tkation
is proving OF functional
a difficult \wtclmtc
task. Accordingly, homologs
the idcnti-
of I~~u.c~~p/~~/o scg-
goal: ni3ny of the icicntificd honiolo~s of I)mrop~i/c/ scgnicntation genes xc nient~~tion gcncs has rciiiaincd
an elusive
I;ntil
tissues
and thus cannot bc con-
as playing ;I role in esrablishing recently.
h3r.e reinforced
the notion
in the in\ erwbratc
tems such as the acquisition rostrocaudal
a nictanicric
the majorit>- of the awilable
axis using
ing b> the I~~ll’4/l~pp
that sqnient;ltion and L crtclmtc ofothcr
ni;ijor
of segment
arow
[1
dara indc-
ph) la. ‘l’hi5 pa~tcrning
identip
Ho.\ sgencs or dorso-\cntral paIh\wy
pNcrn.
niolccular
is
sys-
along the pmm-
Somitogenesis
‘I’his idea of indcpcndent
in\,ertcbrate-~ertet)rate
origins for
segmentation has been challenged recently bp results obtained lvith vertebrate homologs of the lh.sophi/~ pair-rule gene h/i/y\1[ 19,20”] and :I chordate homolog of rhc segment polarity gene mgmihf [21”]. In Zh.sophi/~~, pair-rule genes arc expressed in the primordia of alternate segments and are the first indication of the metameric organi/.ation of the embryo. L’crtebrate homologs of Ihsophih hi/y have been identified in se\wal species including the zcbratish (da./) and chicken (&/iq/). shokvn to be dynamically
In both spwies, these genes were expressed in the I’ShI. In zebnlfish,
/Iw/ is expressed in ever) other somite primordia and thns follows a pair-rule pattern [IV]. ‘I’his 0bserKNion is striking 3s all other pair-rule homologs identified thus far in vertebrate and in\ertcbrate species (except ‘Iiibolium) do not exhibit 3 honiolojis pair-mlc expression pattern [ 22.231. Accordingly, of rww-skip/d and /~‘~.shi-7iu~~~are not expressed in 3 pairrule fashion in the grasshopper [Z-W] and c-h/i/y/ does not exhibit such an expression pattern in the chick embryo [20”]. ‘I’hereforc. until further e\idcnce for the existence of pair-rule segmentation p;w3ns is provided, this issue nilI remain a subject of contro\.ersy Ncverthelcss, the fact that //l/i/-yrelatcd genes arc exprcssfzd in actively segmenting tisSW in both insects and vertebrates suggests a possible conser\ation
of their role in this process
[26.27].
.Anothcr rlnexpcctcd finding implicating the cxistencc of common segmentation mechanisms employed by l~rotostomcs anti dcntcrostomcs h;ls come from the analysis of an .itt/phio.w.s homolog of the Dro?;ophi/c/ segment-polarit> g:e n c qqruikff [ 2 1“.27]. In se\,erul invertebrate species, mymikf/ is exprc3scd sclecti\.ely in the posterior p3rt of body segments where it plays a role in defining segment boundaries [2X]. In the primitive chordate ;h~hiosu.s, mqruih’was found to IX expressed in the caudal domains of the first tight anterior-most somites. A similar exprcssion pattern for an f,//~~/~/i/~,~/liolnologin \.crtebratcs has not been ancy
obser\wl. One possible explanation for this cliscrcpis that this somitic region in .-l~~~p/riosu.s may corre-
spond to the ptiraxial mcsoderm in the hczl region of \wtebratcs u hich does not form owrt somites though it later becomes secondarily segmented [ZY]. It should bc kept in mind that altholrgh expression of the n!i~~mi/c’c/ gents is not restricted to the posterior somitic compartmcnt of \,ertcbrates. these genes ;trc uxprcssed in the de\ eloping somites [.30-321. ‘I’hesc results suggest that some 1wtcbrate homologs of the Dmrophilcl segmentation genes could bc in\wl\,cd in \,crtcbrate somitogencsis, indicating a dcgrec of conscr1’ation bct\veen the segmentation mechanisms of these diffcrent organisms. ‘1%~ clllsisic genetic hierarchy in\ol\wJ in /1l./i,il)/)//i/N segmentation. howc\w, is tlnlikcly to bc conscr\,ed as strch.
A molecular clock linked to segmentation Soniitogcnesis in \wtcbrates compfiscs se\~~al intcrrelatcd procewcs. ‘I‘hc first is the gcncration of a basic niet;mirric or
pwiodic
pattern,
which
McGrew and Pourquib
is morphologically
e\.ident
489
in the
somites and in their segmented derivatives such as vertebrae or muscle. A second is the genetic specification of segments, which is likely to occur at the level of the rostral-most PSXI ;1s suggested I-))-the formation of segmented domains of gene expression which prtzfigure the prospective anterior and posterior somite compartments [33’]. A third aspect of somitogenesis which is independent of the previous one is the formation of the epithelial somite which occurs in response to ectodcrmal signals [33*,3-I’]. A final step is the coordination of somite formation which results in this symetrically bilateral highly rcgnlar pattern. All these steps ocwr in the PShI awl Ltre independent of later somitc differentiation. Several
theoretical
models
which
attempt
to incorporate
all different aspects of somitogcnesis h;i\~ been proposed [X]. Some models suggested the existence of 311 oscillator or clock in the presomitic cells which regulates somtogenesis. ‘I’hese include (:ooke’s ‘clock ;tnd wavcfront’ model [3h]. \Ieinhardt’s model [37]. and Stern’s ‘cell cycle’ model [Ml. ‘I’he purpose of such ;I clock nwuIJ be to gcncrate :I temporal periodicit): which could then be translated into the basic spatial mctameric pattern of the somites. Recently, the study of the expression of an a\%m homolog of hi/-y called ~-hNyZ in the presomitic mcsodorm has provided molecular cvidencc for the existence of such :I clock in these cells [ZO“,39]. c-hi/y1 m RNA is expressed in 3 very dynamic AI’ expression sccluencc in thr I’S‘21 \t.hich is reiterated once during the formation of each somitc (Figtlrc 3). Expression first appears in a broad domain cutending candall~~ Jown to the prospecti\ c tail-bud region. ‘I’his expression domain progressiveI> sweeps anteriorly \\ hilt narrowing. to finally resolve into ;I half somitz size &main bvhich fii\.es rise to the c;1w dal half of the forming somite lvherc cxprcssion is then maintained.
‘I’hc
indcpendcnt
of ccl1 nio~~cnients
the propagation
rather there.
corresponds As &~i/yI
dynamic
wa\vfront
of expression
and does not result
is from
of a signal
in the plant of the I’SIL~ but to an intrinsic property of the cells exprrssion s\vecps across the length of
the entire presomitic mesoderm during the formation of t‘\wy somite. all I’SRI cells will experience a /duiqll ‘on’ and ‘off’ phase during this inter\-al. I3etween the moment a cell bccomcs specified to a paraxi3l mesodcrm fate nnd enters the I’ShI and the moment becomes incorporated into a somitc,
this
cell
actually
12 nc\v somites \vill be formed in the chick cmbr)o [-IO] (I;ignrc 3). ‘I’herefore I’SRI cells \vill undergo 12 cycles of I.-//N~J:~/ expression before brcoming incorporated into ;I somitc. ‘I’hcse oscillations of the ~-/rtliyI mRN’r\ in the PShl ha\,e been proposed to signify a molecular clock linked to somitogtznesis [20”]. It appears that c.-/ItziyI is more tikcly to correspond to ;1 clock product than a key clock component. One of the most rcmarkablt: propertics of this oscillatory brha\iour of the I’SRI cells is \vithont doubt its co-ordination in time and space \\.hich results in its w;~~‘t: like appearance. It u.ill no\\’ lx important to
490
Pattern formation
and developmental
mechanisms
Figure 3
lh30
min
(a)
R
/
(b)
SI P S M
-
Oh 1 h30 3h
1 Oh30
I
12h 13h30
C
15h
16h30
18h
mRNA c-halryl
0
2
1
3
4
5
6 Somite
7
8
9
IO
11
12
number Current Opman r Genetics& Developm~nl
c-hairy7
expressron
expression directron
in the PSM defines
(shaded
areas) appears
in a narrower
newly formed becomes
domain.
c-hairy1
somite;
St,, next oldest
tncorporated
Into a somite
somrtes
present
mRNA
expression
In the presomitic somitrc
expressron
resolves
somrte. (b) History
(a) Durrng the time required
mesoderm.
of a PSM cell (black spot) from the moment
Thus, this cell wrll expenence
rn (b) during the period
compartment
to form one somite
regron of the embryo
into a caudal somrtrc domarn In whrch expression
(18h). This time Interval corresponds
rn the cell illustrated
the cell IS in the caudal
a clock lrnked to somitogenesis.
as a wave arrsing In a broad domarn from the posterior
It resides
to the formation 12 c-haryl
IS maintarned.
it ends gastrulation
waves C, Caudal;
rn a rostra1
S,, formrng
expressron of the c-hairy7
It
of presumptrve
R, rostal. (c) Oscillatrons
These oscillatrons
somrte; S,.
(Oh) untrl the moment
of 12 somrtes, whrch IS the number
in the PSM. At the 12th cycle, chary1
or turns ‘off’ If It is rn the rostra1 compartment.
cell of the PSM and define a clock linked to somite segmentation.
(1 h 30 mm), c-ha~y1
and progressing
of the c-hairy7
erther remarns ‘on’ If mRNA
occur
rn every
Somitogenesis
;lnal~sic
this
dispersion made
clock
at
the
single-ccl1
cxpcrinients
to
cell-~i~itonomo~is
11)
nication
in this
le\,cl
evalu;itc
txh3\
ccll-
tlllmu~l~
the
McGrew
and Pourquit+
491
Figure 4
contribution
ior and cell-cell
commw
D/l 1
pl-occss.
Notch 7
Notch2
RBP-Jk
Mew2
Molecular aspects of somitogenesis: role of the Notch-Delta pathway 01 cr clic past fen- yin, iii~di progress Iix Ix3m matic in the iinclci-~tandinfii~liii~ ofgcnctic
mechanisnis
guiding
somitogencsis
of ,q:ciic Imocl~-out cyxzrinicnt5 in the inousc. ‘liil)lc 1 lists wine of tlic IIIOIISC mutation5 n.liich gcncratcd o\wt dcfccts in somitogcncsis. Quite tinc\;pcctcdthi-oygh
II\C
the
Il. mice in \vhich the nc~irogcnic ,gcncs of the Notch-IkIt Gfpalliiig pcliway sidi as .\/INh/ [Al .-I?]. fMfN1 ]43’*], /?/I/‘,jh ]-l-l] orpmw/i/i/// [4.5”] ncrc linocked omit cdiil~it ;I strong 4c,qncii~;itioii I~hcnorvpe. I;igurc 4 ciiapan~s the csprcssion pttcrn
~cncs
of tlicsc
t‘c\\ ;Intcrior ~ariablc
somite\
sent hit
iiior~~~iologic~II
~:cnc\
lid \oniita
hit
.\ltcrnati\~cl~. wniitcs
might
somites not Ix
in thcsc
important
I-athcr for co-oi-dinatin~ 2 scpirarc
antcrioi-I!
the soniitic
Ic\xI.
and c\-hibit
the .\I’
;i\is
intri,qlin,ql~.
formed
Ix crw_hl
iqq this pith\\:I!
in defining
I\ hich
ii to Ix
‘l‘hc
[.i.i’].
Notch-I
klt:r
half-soniitc indcpcndcnt
pltll\\a)
idcntitics.
similar
injection
ofI\
to thcsc ild-t\
ucrc
ohraincd
or for
it
form;irion for cooi-dimtin,__ (r vmitc of :mtcrior and posterior soniitc
I
pttcrn
SCCIII~ to Ix 31ici t>)r tlic spcc-
rarhcr
CoiiiI);irtinCiiIs.
in .\j/lyW~.i
in \\hich
c (\\ IIci-c iiiolccw
pc oi- dominant-ncgati\
a process
of somitc
dots
morpho~:cncsis,
hi- modit~c~ition results in ;I doniinant loss of protein fuiiction) \ crsions of3 Iklta I~o~iiolo,~. S-c/d/c/Z. 0 r cf 3 .s~~/pmw of’h/i/h:u l~o~nolo, cr Icd to dimiption of iii\otoiii;il scgiiicnt~ltion. 5ufific\tin g 2 coiiwn ccl I-olc for this p:rrli\\ ;I\ in co-oi-tliixiting L crtclmtc son~ito~ciic~i~ [-I~~“~.
Iising cithci- n~\otomal OI- wIcrotoiii:iI ni:irkm rc\cdcd 2 rcsiclilal. alkit ii-i-qular. scgtncnral distril>rition: ho\\ c\ cl-. tlic .\I’ sulxli\~ision of tllc siCIcrotonic i\ found I0 1x1 p~-~~fou~icll~ affcctcd. (hiscc~ucntl~, the scgnicntxion of tlic pci-iphcr:ll iicr\ 011s system i\ ,~ w)sslv :ilmmiial. implicatmcsodcrni
was \Iio\\
wniitc
rccluired
of the pmxial
the IxiGc mctamci-ic
for cstal,lishing
ification
mutants
of
somltes.
cpithclial
pc.
iii thaw
PSM of
cpithc-
morl~‘hogcncsis.
21) corild Ix utiliscd to spwitj i-cdundanc~~ mighr rcscuc part of
aiial~~is
areas) in the mouse
suggest
for making their
(shaded
genes Important for somltogenesis. The knock-out many of which belong to the Notch-Delta pathway,
results In severe somltogenlc defects. The expression patterns of some of these genes define restricted domalns In the PSM and in the newly
is
padi\\
or gcnc
phcnoty
muLint
patterns
representative these genes,
mutants
of ~incoortlillatcci
thar thcw
hlorc
I,lit arc ~~ncoortlin~rtcd
Expresslon
:I
xnd pt-;~~ial nicsoclcrni i\ prc3nci tail soinircs arc wiually not ol~sm cd. ‘l’hc
in thcsc
trunk
prcwnrc
form
.\t ;I grch\
sks.
c~t~il~lishcd
I’SJI. In 211 thcsc inutaiih
in the
In\ OIL cinciiI of tlic Uotcli-I klt:i si,qii~rllin,g patliwa) in rcgLrlating scgincnt formation scciilh to Ix ;I clcir c;isc
fol-m&m
Ilot tllcrcfol-c
\,cCIll to
Table 1 Mouse knockouts displaying severe defects in somitogenesis. Gene targeted
Somltlc
phenotype
Reference
FGFRI
Expansion
Tbx6
CranIaI somltes
w/J t-3a
Loss of caudal
Notch 1
Irregtllar
Delta
Irregular somlte formatlon; segment polanty dlsrupted
1 fD111)
of axial mesoderm present somites;
somltes.
at the expense
but Irregular, paraxial tissue
basic metameric
of paraxial mesoderm;
remaIring
paraxlal mesoderm
may be replaced
pattern
establlshed;
basic metamerlc
pattern
[61
loss of all somite formatlon lost and replaced
by neuronal
tissue
by tissue segment
established;
WI polanty
disrupted;
somitlc
llneages
normal FGFRl
expresslon
141,421
are present; [43’1
Irregular somltes with Increasing seventy In posterior embryo; basic metameric pattern establlshed; somitic llneages are present; segment polanty disrupted; loss of Notch7 and D//l in PSM RBP-Ik
Irregular somltes; presence segment polarity dlsrupted
Mesp2
Irregular somlte formation; basic metamerlc pattern establlshed; somatic lineages segment polanty disrupted; loss of Notch7 and FGFRl expression
Param
No epithellal
somtte
c7.1
of dermomyotome
but metamerlc
and sclerotome
although
no myogenin
expresslon
[45’1 detected; [351
units are apparent;
somltlc
lineages
are present;
are present
[49’1 [501
492
Pattern
whcrc
formation
vcrtcbrates
Ixen
reported
and developmental
and
tly differ ;I role
to pIa)-
role for this signalling
mechanisms
since
in fly
these
gents
ha\xz
scgnientation.
not
:\ major
system in f~m.coiO/li/f~is in the control
of cell-fate choice in the lateral inhibition process u hich has lxcn u cll-descrihcd for the formation of the pcripheral ner\ 011sr);stem [47]. ‘I’hc defects in comite antero-postcrior
in Ketch-Iklta pathway mutants, suggests that the role of this path\\ a? in L erte-
specification
ho\ve\u-, I)rates
might
used,
be niorc
for instance.
wing
margin
related
in the
to boundar)
establishment
definition
of the
3s
Z~MJSO~A~/~~
[4X].
References and recommended
l
scription
factors
in
somitogenesis
rlcnionstratcd.
‘I’hese
;irc cxpresscd
3s ;i stripe
tlcrni
factors
(see Figure
has
include
in the
and the /M/~L/SIS gene
the I’Shl
which
of the trunk
soniitc
deri\xtiI~cs
proceeded
the
In conttxt
posterior
sclcrotonie
appears
Illllt;lllt
:\dditioixill~, is
lost
to
lac!i
the
the
I’S\1
in
lies upstruni
thcsc
of these
is
anterior
factors.
of
Gossler A, Hrabe de AngelIs M: Somitogenesis. 1998, 38:225-287.
3.
Catala M, Telllet MA, Le Douarln NM: Organization and development of the tail bud analyzed with the quail-chick chimaera system. Mech Dev 1995,51:51-65.
nor-
4.
Psychoyos D, Stern CD: Fates and migratory routes of primitive streak cells in the chick embryo. Development 1996, 122:1523-l
in \vhich
lacking.
this
coimpartnient.
niutants,
development.
2.
\vhilc
fairI)
and .\‘ot/fi/
of /+‘(;FR/
nicso-
pattern
knock-out,
conipartnicnt
txprcssion
from
hlcsp7
to the IId~~~/
Christ B, Ordahl CP: Early stages of chick somite Embryo/ fi3erl) 1995, 191:381-396.
Anat
Curr Top Dew B/o/
throughout
diffcrcntiation
[-We].
1.
\vhich
IIIOIISC knock-out
.l/~sp.! led to ;I disruption mally
IXXXI
presoniitic
is cxprcssed ‘I’he
of special interest * of outstanding Interest
tran-
recently
the .Uesp gcncs
rostra1
1) [-W”,SO].
of soniitic
l
I (basic hcli~-loop-helix)
role for b-HI,1
.A significant
reading
Papers of particular Interest, published wlthin the annual period of review have been highlighted as:
2nd AVofcfil
suggesting
SimilarlyT
that
the niilu-
534.
5. Richardson MK, Allen SP, Wright GM, Raynaud A, Hanken J: Somite . number and vertebrate evolution. Development 1998, 125:151-l 60. This review examines the variation ot somlte number between animal species. The authors propose that the process of somltogenesls shows a ‘dlssoclatlon’ from the ‘developmental hourglass’ model. 6.
Yamaguchl TP, Harpal K, Henkemeyer M, Rossant J: fgfr-1 is required for embryonic growth and mesodermal patterning during mouse gastrulation. Genes Dev 1994, 8:3032-3044.
rctainccl
7. .
Chapman DL, Papaloannou VE: Three neural tubes in mouse embryos with mutations in the T-box gene Tbx6. Nature 1998,
(see
This study demonstrates that Tbx6 IS necessary for the proper specification of the posterior paraxial mesoderm. The targeted mutation of Tbx6 resulted In the apparent conversIon of posterior paraxial mesoderm into neural-tube-like structures.
tion
of
the
somitc
p/u/.\ii
gene
forni~ition
hiit
rcsilltcd
in
paraxial
a complctc
niesodcrni
loss of
deri\ati\
cs
;I scgimcntal organisation [.50]. Kesults siicll as thcsc ha\,c lmnidecl c\,idencc that the process of soniitopicsis can he dissociated from wrtclxate segnicntation >llSO [I3.1,.
Conclusions ‘I’he
identification
tion
of the paraxial and
7%x6,
for
Notch-Iklta
of genes important mesodcrni
its
has pro\ iclcd insight togcncsis. point
into
Kcccnt
to the
Iq ~lIui/yl
iiiiportancc
nicdi:rtecl
studies
of both 11)
hy
the
and
of
the
gents
go\,crning on
sonii-
somitogcnesis
the autonomic
hclia\
internal
e\idcnced
an
clock
and to the role of cell-cell
oscillations
nications
lli/L?.d
as those
the mechanisms
molecular
cells as rcgiilatcd
of I’Shl
such
.Ilr~.sp:l,l./)N~~N\./.cand /Ioiy-like
pithway.
8. .
for Carla spccifica-
such ;is I~‘G/;KI,
segnientation
kotcll-l>clt:l
of somitc
and posterior
anterior clock icity of
could u hich
the
\1.hctllel-
brates
Ix
these
soniitic
translated ITin;illy.
path\\~a);s
in in\wtebratc
\\.hich
and
path-
generate
of soniitogencsis.
into it are
spxification
coniprtrments
will
the spatial be
conscrked
species scgnients
such
IO.
Marcelle C, Stark MR, Bronner-Fraser M: Coordinate actions of BMPs, Writs, Shh and noggin mediate patterning of the dorsal somite. Development 1997, 124:3955-3963.
11.
DIetrIch S, Schubert FR, Lumsden A: Control of dorsoventral pattern in the chick paraxial mesoderm. Development 1997. 124:3895-3908.
12.
Boryckl AG. Mendham L, Emerson C: Control of somite patterning by sonic hedgehog and its downstream signal response genes. Developmenf
1998,
125:777-790.
the
pcriod-
13.
Tajbakhsh S, Cossu G: Establishing myogenic identity during somitogenesis. Curr Opm Genet Dev 1997, 7:634~641.
14.
Tajbakhsh S, SpBrle R: Somite development: vertebrate body. Cell 1998, 92:9-l 6.
15.
Christ B, Schmidt C, Huang R. Wilting J, Brand-Saber1 B: Segmentation of the vertebrate body. Anat Embryo/ (Bedi 1998,197:1-8.
16.
Sander K: Specification of the basic body in insect embryogenesis. Adv insect Physol 1976, 12:125-238.
arrangenicnt
interesting in
Hlrsinger E, Duprez D, Jouve C, Malapert P, Cooke J, Pourqule 0: Noggin acts downstream of Wnt and Sonic Hedgehog to antagonize BMP4 in avian somite patterning. Development 1997, 124:4605-4614.
of
\\.hereas
g a tcniporril
9.
coiilmii-
signalling
in the
in\ ol\ cd in gencratin
is later
soniitcs. and
annclids cent
niorphogenesis
Yoshlkawa Y, Fullmorl T, McMahon AP, Takada S: Evidence that absence of Wnt-3a signaling promotes neuralization instead of paraxial mesoderm development in the mouse. Dev Biol 1997, 183~234.242. This report details the analysis of Wnt-3a mutant mice. Similar to the results shown above [7’1 with the Tbx6 knock-out, Wnf-3a mutant embryos do not correctly form paraxlal mesoderm; Instead an additional neural tube-llke structure IS generated medially.
ioiir
bay. ‘I’hc link Ixavccn these two systems has not yet hccn cstablishcd but it is rcasonahle to hypothcsizc that the clock ;Icts ripstrcani of the Ketch-lklta path\3xy. ksiilts from nioiisc: knock-out cxperinicnts strggcst that the latter system is iiiorc likely in\wl\d in the co-ordination
391:695-697.
other
to
xx
\wte-
as grasshopper
in a manner
rcniinis-
or
constructing
the
Somitogenesis
1 7.
Kornberg TB, Tabata T: Segmentation of the Drosophila Curr Opin Genet Dev 1993, 3:585-594.
18.
DeRobertls EM, Sasal Y: A common plan for dorsoventral patterning in Bilateria. Nafure 1996, 380:37-40.
19.
Muller M, von Welzsacker E, Campos-Ortega JA: Expression domains of a zebrafish homologue of the Drosophila pair-rule gene hairy correspond to primordia of alternating somites. Developmenf 1996, 122:2071-2078.
embryo.
Palmelrlm I, Henrique D, Ish-Horowlcz D, Pourquie 0: Avian hairy gene expression identifies a molecular clock linked to vertebrate segmentation and somitogenesis. Ceil 1997, 91:639-648. A report of the ldentlflcatlon of an avlan harry homolog which IS expressed IIa dynamic and cyclic fashion In the presomitlc mesoderm. It IS proposed that the oscillations of the c-hairy1 mRNA in the PSM identify a molecular clock linked to somltogenesls. The purpose of such a clock would be to translate a periodic temporal pattern into the spatrat penodicity of somltes. This gene IS, however, not expressed in a pair-rule fashion in the PSM. 20. .
21. .
Holland LZ, Kene M, Williams NA, Holland ND: Sequence and embryonic expression of the Amphioxus engrailed gene (AmphiEn): the metameric pattern of transcription resembles that of its segment-polarity homolog in Drosophila. Deveiopmenf 1997, 124:1723-l 732. An Amph~oxus homolog of the engrafled gene and Its expression pattern IS described.. Surprlstngly, this gene IS expressed In the caudal part of the head somites which IS slmllar to the arthropod system In which engrailed IS expressed in the caudal part of segments. This observation relnforces the Idea of a potential conservation between the segmentation mechanisms used by protostomes and deuterostomes. 22.
Akam M: Insect development. 367:41 O-41 1.
Is pairing
the rule? Nature 1994,
23.
Pate1 NH: The evolution of arthropod segmentation: insights from comparisons of gene expression patterns. Development 1994, SuppI.: -207.
24.
Pate1 NH, Condron BG, Zlnn K: Pair-rule expression patterns of even-skipped are found in both short- and long-germ beetles. Nature 1994, 367:429-434.
25.
Dawes R, Dawson I, Falclanl F, Tear G. Akam M: Dax, a locust Hox gene related to fushi-tarazu but showing no pair-rule expression. Development 1994, 120:1561-l 572.
26.
Klmmel CB: Was Urbilateria 12:329-331.
27.
De Robertls EM: Evolutionary biology. The ancestry of segmentation. Nature 1997, 387:25-26.
28.
Pate1 NH, Martin-Blanco E, Coleman KG, Poole SJ, EIIIs MC, Kornberg TB, Goodman CS: Expression of engrailed proteins in arthropods, annelids, and chordates. Cell 1989, 58:955-968.
29.
Schllling TF, Klmmel CB: Musculoskeletal patterning in the pharyngeal segments of the zebrafish embryo. Deveiopmenf 1997, 124:2945-2960.
30.
Fjose A, Njolstad PR, Nornes S, Molven A, Krauss S: Structure and early embryonic expression of the zebrafish engrailed -2 gene. Mech Dew 1992, 39:51-62.
31.
Davis CA, Holmyard DP, Mlllen KJ, Joyner AL: Examining pattern formation in mouse, chicken and frog embryos with an Enspecific antiserum. Deveiopmenf 1991, 111:287-298.
32.
Gardner CA, Barald KF: Expression patterns of engrailed -like proteins in the chick embryo. Dev Dyn 1992, 193:370-388.
segmented?
Trends Genet 1996,
33. .
Palmerrim I, Dubrulle J. Henrlque D, Ish-Horowlcz D, Pourqule 0: Uncoupling segmentation and somitogenesis in the chick presomitic mesoderm. Dev Genef 1998, 23:77-85. The authors show that explants of avian presomltlc mesoderm devoid of surrounding structures can exhibit a segmental pattern of c-Delta-7 and cNotch-l expression In absence of somlte eplthellalizatlon. In addltlon, It IS shown that ectoderm can restore somite formation in these explants. 34. .
Sow D, Brand-Saber1 B, Schmidt C, Christ B, Olson EN: Regulation of paraxis expression and somite formation by ectoderm- and neural tube-derived signals. Dev Biol 1997, 185:229-243.
McGrew
and Pourqulb
493
This report uses surgical manipulations such as in v&o ectoderm ablation In the chick embryo to demonstrate the role of ectodermal signals in promoting paraxis expression and somite eplthelializatlon. 35
Keynes RJ, Stern CD: Mechanisms Developmenf 1988, 103:413-429.
36
Cooke J, Zeeman EC: A clock and wavefront model for control of the number of repeated structures during animal morphogenesis. J Theor B/o/ 1976, 58:455-476.
37.
Melnhardt
of vertebrate
segmentation.
H: Models of segmentation. In Somites m Developing Edited by BellaIrs R, Ede DA, Lash JW. New York and London: Plenum Press; 1986:179-l 91.
Embryos.
38
Stern CD, Fraser SE, Keynes RJ, Prlmmett DR: A cell lineage analysis of segmentation in the chick embryo. Development 104:231-244. a theory-somitogenesis 1998, 14:85-88.
1988,
39
Cooke J: A gene that resuscitates molecular oscillator. Trends Genef
and a
40
Packard DSJ: The influence of axial structures formation. Dev B/o/ 1976, 53:36-48.
41
Swlatek PJ, Llndsell CE, del Amo FF, Welnmaster G, Gridley T: Notch1 is essential for postimplantation development in mice. Genes Dev 1994, 8:707-719.
42
Conlon RA. Resume AG. Rossant J: Notch1 is reauired for the coordinate stgmentation of somites. Develop&f 1995, 121 :1533-l 545.
on chick somite
Hrabe de Angelis M, McIntyre J, Gossler A: Maintenance of somite borders in mice requires the Delta homologue DIII. Nature 1997, 386:717-721. This paper shows the major role played by Delta1 m somlte patterning. The targeted mutation of this Notch ligand results In the loss of somlte polarity whereas the derivatives of the somites form normally. A possible consequence of the loss of segment polarity IS the disruptton of somite borders. 43 .
44.
Oka C, Nakano T, Wakeham A, de la Pompa JL, Man C, Sakat T, Okazaki S, Kawalchl M, Shlota K, Mak TW, Hon~o T: Disruption of the mouse RBP-J kappa gene results in early embryonic death. Development 1995, 121:3291-3301,
45. .
Wong PC, Zheng H, Chen H, Becher MW, Slrmathslnghjl DJ, Trumbauer ME, Chen HY, Price DL, Van der Ploeg LH, Stsodia SS: Presenilin 1 is required for Notch1 and Dill expression in the paraxial mesoderm. Nature 1997, 387:288-292. The authors report that the major defect caused by the targeted mutation of presentltn 1, a modulatlor of the Notch signalmg pathway. is a dIsruptIon of somltogenesls. The accompanying reduction of Delta1 and Notch7 In the PSM is suggestive of a role In the regulation of these factors. 46. .
Jen WC, Wettsteln D, Chltnls D, Klntner C: The Notch ligand, XDelta-P, mediates segmentation of the paraxial mesoderm in Xenopus embryos. Deveiopmenf 1997, 124(Suppl.):1169-1178. This study IS the fwst to describe the expression of the Xenopus delta homolog, X-Delta-2, as a senes of stripes In the PSM. The authors show that the overexpresslon of a dominant negative form of either X-Delta-2 or suppressor of harless, XSu(Hl, disrupts segment formatlon. These results suggest that, In Xenopus, the Notch-Delta pathway plays a role In segment formation. 47.
Klmble J, Simpson P: The LIN-1 S/Notch signaling pathway and its regulation. Annu Rev Cell Dev B/o/ 1997, 13:333-361,
48.
Blair SS: Limb Development: 1997, 7:686-690.
marginal fringe benefits. Curr Biol
49. .
Saga Y, Hata N, Kosekl H. Taketo MM: MespP: a novel mouse gene expressed in the presegmented mesoderm and essential for segmentation initiation. Genes Dev 1997, 11 :1827-l 839. These authors demonstrate that the b-HLH factor, Mesp2, IS required for somitogenests. The targeted knock-out of this gene disrupts somlte formation and segment plolarlty. Evidence is presented which suggests that MespP may lie upstream of the Notch-Delta and FGFRl slgnalmg pathways In the PSM. 50.
Burgess R, Rawls A, Brown D, Bradley A, Olson EN: Requirement the paraxis gene for somite formation and musculoskeletal patterning. Nature 1996, 384:570-573.
of
Somitogenesis:
segmenting
Michael J McGrew*
a vertebrate
and Olivier Pourquikt In man) \ crtcbfiltc species such ~1s the chick, :III~ zebrafish. somitcs form as cpithetial sphcrcs \\.hich l)ud off in a highI>- co-ordinated fashion from the \ crtcbrates.
The partitioning of the vertebrate body into a repetitive series of segments,
or somites,
~nouse
requires the spatially and temporally
co-ordinated behaviour of mesodermal cells. To date, it
rostra1
remains unknown how applicable our knowledge of the genetic mechanisms
governing Drosophila
be to that of vertebrates, though recent results degree of conservation.
Genetic studies
a major role for the Notch-Delta formation. the
Furthermore,
presomitic
indicate some
in the mouse point to
signalling pathway in somite
a molecular
clock
may
be ‘ticking’
in
Addresses Laboratolre de GBn6tlque et de Physlologie du D&eloppement (LGPD), Developmental Biology Institute of Marseille (IBDM), INSERM-UniversitB de la m8diterran&AP Lumlny, Case 907, 13288 Marseille Cedex
de Marseille, 09, France
de
C’ Current
in Genetics
Biology
I)iirin,<
& Development
Publications
ISSN
1998,
the this the ahI>
8:487-493
0959-437X
basic helix-loop-helix fibroblast growth factor
PSM
presomitic
contr;tst.
littlc
somitogcnesis
scgnicntul
clurin, (7 which
of the xrtcbratc
body
rcccntl~.
I:irst,
,q of ttic
the
1~~x1. In
about the proct‘ss
the basic sejinicnted Se\xxit
scgmentntion,
althou!:h
at the espcnsc the knock-oiit
se\,cral
of
pattern important
ho\\c\.rr. haIre major
patternin::
Soon terncd sues
2fter
their
to min,
the
of the lxiir-rule is discussed
system
obscr\ed
formation.
in rcsponsc [SlZ].
mesodcrni
[6]. hlore
of ‘Ifix
-
3 lxx+!
fxtor
-
ted to the app;lrcnt
ury-like
‘II
cpithcliat soniitcs
compartnicnt
I\ hich the x&II
in
here. \\~eIIISO discuss
sonlitcs
Ixconie
pat-
to loc~it signals from the surrounding
\cntrall!.
mescnch~inat
slxlcton
differcntiatc
called
Llriscs.
the
sclerotomc
and dorsalI>
tis-
into
into the dcr-
[.?.13,14].
cpithclial
On the basis of the differential
ious jicncs.
ncn4y formed cpithcti:il
to possess
anterior gi\ c rise
csprcssion
somitcs
of \;lr-
can bc consid-
and postcrioi- comp;irtments which to ;I \.isil)le ~intero-l~ostcrior (A[‘)
:i rcccntl\ idcntificd nioleciil:iiclock linked to \crtclmtc scgnicntation \\ hich pro\ ides molecular support for SC\ craI theoretical models of somitogencsis. I’urthcrmorc. SC\ cral targeted miitations in niicc ha\.c pro\ ided increasing c\ idcncc fol- 3 central rote of the KotcbI1clta signatlin,g lxith\\.a!, in the control of somitogcnesis.
sclcrotonic siilxii~.ision. ‘l’his siibclidsion wilt pro\,ide the Ixlsis for ;i law rt”scgnicntation proccs\ during diich the \ crtcbrac arc fornicd from the fusion of a caudal half soniitc n-ith the rostral half of the next soniite [1.5]. ‘I’hus. the jicncration and patterning of the soniites reclLiircs the integr;ition of niorphogenctic lxithwq3 with those go\ crnin,q cell fate. coml~~irtiiientali/ation . and tincqc slxcit~cation.
Origin and formation
Segmentation
/)mw~/Ii/~~
Somitcs th;it
;irc
scgmcnt:ltion
are transient prcscnt
in
of somites
scgmcnts dc\.clopiii::
of the pxixi:il
mcsodcrni
Sc~nicnt3tion
and
tic of ni:in\
CCl’h:ilochord;ltcs
3
from
and yields the hod) skctrtal ~~IISC~~S and prt of the dermis. It is beyond the scope of this rc\-ic\\ to discuss somitc lxittcrnin,g and the rcadcr i\ cncoiira,qed to conslilt the follo\ving rc~itxr’s
siitxccliicntt!
in son~itogcnesis
primiti\,e
nicsodcrm
momg otoiii6’ \\4iich rcixiins
cmbr\-0l;encsis
l)mrl,l’/‘i/0
allocated to
rostrat
rccruitcd
of paraxial
tr:lnscription
of p:ir;i\i:il
crcd
during
the
phenot>,pc uxs
nicnt
utitised
cells lxxomc
through
in de\~clopnicnt.
siirprisingl!.
becm to ha\ e been issue of \vhethcr 5ejinient:rtion :irosc indepcndentl~ in protostoimcs and dclitcl-ostonies rcniains ~1mittcr for spiritcd dcbatc. LSonic rcccnt olmm~ations offu siipport for the cxiswncc of ;I conscr\ cd nicch;inisiii: in particular. the possibtc in\ot\xs)5Wms
conscr\,eci from
of the
l)mwp~il~~
niolccular
is est:iblishcd.
issue’s rete\ Lint to \ crtebrate ;u-iscn
is known
numtxr.
into neur:it tissue [7”]. .A also reported for the txgcted niiitation of the secreted t:,ictor L\.nt-.3;i [Y]. ‘l’hese rcsutts suggcst that intricate si~n:illing p;ith\\x3 exist to direct ne\vl~ irlgrcssin,? cells to a pii-axial niesoderm fate.
Ixtttcrnin
\\xll understood ;It is Ic~iow~i moleciilarl~
nothing sornitc
in amniotes,
injircssion
nicsoderm
similar
mesoderm
of
i\ no\\’
\‘irtuatly
controlling
cells dcri\ze from tail bud. Sawit targctrd niousc mutations affecting prowss ha\c irecentl! l~cn idcntificct. For exanipte, niiit;ition of /~‘(~/~‘/?I ~rrsiitted in a toss of soniitcs, prob24 :in indirect co~ise~luxcc of the cllxinsion of axial later
con\,ersion receptor
Introduction Specification
after
I,()~-cont:liniri~
b-HLH FGFR
[S’].
fi;istrulation
I’Shl
\trcak;
Abbreviations AP antero-postenor
cnlt)r)o
species processes
the
Olivter Pourqul&
Opinion
I!- rel:itcd molccul;ir CNRS-
Campus
*e-mall: [email protected] .‘e-mall: [email protected]
Current
mal presoniitic niesoderni (I’Shl) [ 1.21. of these structures projircsses rostro-c;i1ictatt~ siiiiiiltaiicolist~ \vith the recruitnicnt of nt’\\’ nicscnch!m:il cells from the site of~astrulation into the caudal end of the I’SYI (I;igiire 1) [.3,-l]. .Soniitogencsis proceeds ;It ;I defined pee \\,hich is both teml’cratllrc-dcpcndent and species-specific. ‘I’he total niimbcr of somites is also . species-specitic and can Ix highly \.ariabte bctn ecn ctosc-
mesoderm.
Correspondence:
niesench)
‘I’hc generation
segmentation will
as a conserved mechanism
or metaineris3tion animal
spccics
is also ii basic characterisother
thin
the
\-errcbratcs.
488
Pattern formation and developmental
mechanisms
Figure 1
Figure 2
Rostra1
c
n
SI
Somite formation
Time Differentiation of somitic derivatives Somlte formatlon
(every 90 mins) c ”
Somites
Segment specification
@
‘P ; M
0 somites
4 somites Presomitic mesoderm
Chick somitogenesis Tail bud
17 somltes
Specification of paraxlal mesoderm fate
Caudal Current
Op~n~an in Genetics
Schematic representation of somite formatlon somlte 0; SI, somite I; SII, somite II.
,
& Development
from the PSM, SO,
Segmented thorax
13ody segmentation in these spwics usually corresponds to 2 rcpctition along the XI’ axis of similar strwtlircs consist-
ing of deribativcs from the three enihr)-onic gum layers. Serial segments are found in the annclid, insect, and \ c‘i-tcbrxc classes bur not in others - such as rhe molluscs and echinodcrn~s. As discussed above. segnient;ition in vcrtebratcs is most olxG)us in the trunk at the le\xl of rhe
Grasshopper segmentation
Fully segmented
\zrtcbral column, its associated muscles, and the pcriphcral nm 0~1ssystcni. Scgnicntation at rhe head Ia cl is found in the I,ranchial
archcs and the rhomlmneres
t,c discussed here. Somite inisccnt
of segmentation
formation
hut ~1ill not
is in many \v;lvs rem-
in short-germ
band insccrs
such
as the grasshopper. in w,hich scgnients arc added coiiscci~ti\xly from ;I rerminal groudi mnc (I:ijitirc 2) [lb]. ‘I’his mode of scgnientation
is in sharp contmt
to that found
Comparison segmentation
between somitogenesls in the chick embryo and In a short germ band insect, the grasshopper. In both
types of organisms,
In contrast
to Drosophila,
segments
are formed
after gastrulation and regularly appear In a rostra1 to caudal progression as the embryonic axls IS laid down. PS, primltlve TGZ, terminal growth zone.
streak;
in
all scgnicnrs are gcncratcd sinirllrancoiisly in a syncitial blastoderni [ 171. /)/v.iop/)/li/~, in uhich
not expressed sidcrrd
in segmenring
Ikcausc of this \‘ery particular niodc of scgnicntation, the transposition of the genetic hierarchy of the \vell-characterizcd /)msop~;/~ segmentation gents to the rest of the animal
pendently
kinjirloni
in contrast Cothe conser\2tion
tkation
is proving OF functional
a difficult \wtclmtc
task. Accordingly, homologs
the idcnti-
of I~~u.c~~p/~~/o scg-
goal: ni3ny of the icicntificd honiolo~s of I)mrop~i/c/ scgnicntation genes xc nient~~tion gcncs has rciiiaincd
an elusive
I;ntil
tissues
and thus cannot bc con-
as playing ;I role in esrablishing recently.
h3r.e reinforced
the notion
in the in\ erwbratc
tems such as the acquisition rostrocaudal
a nictanicric
the majorit>- of the awilable
axis using
ing b> the I~~ll’4/l~pp
that sqnient;ltion and L crtclmtc ofothcr
ni;ijor
of segment
arow
[1
dara indc-
ph) la. ‘l’hi5 pa~tcrning
identip
Ho.\ sgencs or dorso-\cntral paIh\wy
pNcrn.
niolccular
is
sys-
along the pmm-
Somitogenesis
‘I’his idea of indcpcndent
in\,ertcbrate-~ertet)rate
origins for
segmentation has been challenged recently bp results obtained lvith vertebrate homologs of the lh.sophi/~ pair-rule gene h/i/y\1[ 19,20”] and :I chordate homolog of rhc segment polarity gene mgmihf [21”]. In Zh.sophi/~~, pair-rule genes arc expressed in the primordia of alternate segments and are the first indication of the metameric organi/.ation of the embryo. L’crtebrate homologs of Ihsophih hi/y have been identified in se\wal species including the zcbratish (da./) and chicken (&/iq/). shokvn to be dynamically
In both spwies, these genes were expressed in the I’ShI. In zebnlfish,
/Iw/ is expressed in ever) other somite primordia and thns follows a pair-rule pattern [IV]. ‘I’his 0bserKNion is striking 3s all other pair-rule homologs identified thus far in vertebrate and in\ertcbrate species (except ‘Iiibolium) do not exhibit 3 honiolojis pair-mlc expression pattern [ 22.231. Accordingly, of rww-skip/d and /~‘~.shi-7iu~~~are not expressed in 3 pairrule fashion in the grasshopper [Z-W] and c-h/i/y/ does not exhibit such an expression pattern in the chick embryo [20”]. ‘I’hereforc. until further e\idcnce for the existence of pair-rule segmentation p;w3ns is provided, this issue nilI remain a subject of contro\.ersy Ncverthelcss, the fact that //l/i/-yrelatcd genes arc exprcssfzd in actively segmenting tisSW in both insects and vertebrates suggests a possible conser\ation
of their role in this process
[26.27].
.Anothcr rlnexpcctcd finding implicating the cxistencc of common segmentation mechanisms employed by l~rotostomcs anti dcntcrostomcs h;ls come from the analysis of an .itt/phio.w.s homolog of the Dro?;ophi/c/ segment-polarit> g:e n c qqruikff [ 2 1“.27]. In se\,erul invertebrate species, mymikf/ is exprc3scd sclecti\.ely in the posterior p3rt of body segments where it plays a role in defining segment boundaries [2X]. In the primitive chordate ;h~hiosu.s, mqruih’was found to IX expressed in the caudal domains of the first tight anterior-most somites. A similar exprcssion pattern for an f,//~~/~/i/~,~/liolnologin \.crtebratcs has not been ancy
obser\wl. One possible explanation for this cliscrcpis that this somitic region in .-l~~~p/riosu.s may corre-
spond to the ptiraxial mcsoderm in the hczl region of \wtebratcs u hich does not form owrt somites though it later becomes secondarily segmented [ZY]. It should bc kept in mind that altholrgh expression of the n!i~~mi/c’c/ gents is not restricted to the posterior somitic compartmcnt of \,ertcbrates. these genes ;trc uxprcssed in the de\ eloping somites [.30-321. ‘I’hesc results suggest that some 1wtcbrate homologs of the Dmrophilcl segmentation genes could bc in\wl\,cd in \,crtcbrate somitogencsis, indicating a dcgrec of conscr1’ation bct\veen the segmentation mechanisms of these diffcrent organisms. ‘1%~ clllsisic genetic hierarchy in\ol\wJ in /1l./i,il)/)//i/N segmentation. howc\w, is tlnlikcly to bc conscr\,ed as strch.
A molecular clock linked to segmentation Soniitogcnesis in \wtcbrates compfiscs se\~~al intcrrelatcd procewcs. ‘I‘hc first is the gcncration of a basic niet;mirric or
pwiodic
pattern,
which
McGrew and Pourquib
is morphologically
e\.ident
489
in the
somites and in their segmented derivatives such as vertebrae or muscle. A second is the genetic specification of segments, which is likely to occur at the level of the rostral-most PSXI ;1s suggested I-))-the formation of segmented domains of gene expression which prtzfigure the prospective anterior and posterior somite compartments [33’]. A third aspect of somitogenesis which is independent of the previous one is the formation of the epithelial somite which occurs in response to ectodcrmal signals [33*,3-I’]. A final step is the coordination of somite formation which results in this symetrically bilateral highly rcgnlar pattern. All these steps ocwr in the PShI awl Ltre independent of later somitc differentiation. Several
theoretical
models
which
attempt
to incorporate
all different aspects of somitogcnesis h;i\~ been proposed [X]. Some models suggested the existence of 311 oscillator or clock in the presomitic cells which regulates somtogenesis. ‘I’hese include (:ooke’s ‘clock ;tnd wavcfront’ model [3h]. \Ieinhardt’s model [37]. and Stern’s ‘cell cycle’ model [Ml. ‘I’he purpose of such ;I clock nwuIJ be to gcncrate :I temporal periodicit): which could then be translated into the basic spatial mctameric pattern of the somites. Recently, the study of the expression of an a\%m homolog of hi/-y called ~-hNyZ in the presomitic mcsodorm has provided molecular cvidencc for the existence of such :I clock in these cells [ZO“,39]. c-hi/y1 m RNA is expressed in 3 very dynamic AI’ expression sccluencc in thr I’S‘21 \t.hich is reiterated once during the formation of each somitc (Figtlrc 3). Expression first appears in a broad domain cutending candall~~ Jown to the prospecti\ c tail-bud region. ‘I’his expression domain progressiveI> sweeps anteriorly \\ hilt narrowing. to finally resolve into ;I half somitz size &main bvhich fii\.es rise to the c;1w dal half of the forming somite lvherc cxprcssion is then maintained.
‘I’hc
indcpendcnt
of ccl1 nio~~cnients
the propagation
rather there.
corresponds As &~i/yI
dynamic
wa\vfront
of expression
and does not result
is from
of a signal
in the plant of the I’SIL~ but to an intrinsic property of the cells exprrssion s\vecps across the length of
the entire presomitic mesoderm during the formation of t‘\wy somite. all I’SRI cells will experience a /duiqll ‘on’ and ‘off’ phase during this inter\-al. I3etween the moment a cell bccomcs specified to a paraxi3l mesodcrm fate nnd enters the I’ShI and the moment becomes incorporated into a somitc,
this
cell
actually
12 nc\v somites \vill be formed in the chick cmbr)o [-IO] (I;ignrc 3). ‘I’herefore I’SRI cells \vill undergo 12 cycles of I.-//N~J:~/ expression before brcoming incorporated into ;I somitc. ‘I’hcse oscillations of the ~-/rtliyI mRN’r\ in the PShl ha\,e been proposed to signify a molecular clock linked to somitogtznesis [20”]. It appears that c.-/ItziyI is more tikcly to correspond to ;1 clock product than a key clock component. One of the most rcmarkablt: propertics of this oscillatory brha\iour of the I’SRI cells is \vithont doubt its co-ordination in time and space \\.hich results in its w;~~‘t: like appearance. It u.ill no\\’ lx important to
490
Pattern formation
and developmental
mechanisms
Figure 3
lh30
min
(a)
R
/
(b)
SI P S M
-
Oh 1 h30 3h
1 Oh30
I
12h 13h30
C
15h
16h30
18h
mRNA c-halryl
0
2
1
3
4
5
6 Somite
7
8
9
IO
11
12
number Current Opman r Genetics& Developm~nl
c-hairy7
expressron
expression directron
in the PSM defines
(shaded
areas) appears
in a narrower
newly formed becomes
domain.
c-hairy1
somite;
St,, next oldest
tncorporated
Into a somite
somrtes
present
mRNA
expression
In the presomitic somitrc
expressron
resolves
somrte. (b) History
(a) Durrng the time required
mesoderm.
of a PSM cell (black spot) from the moment
Thus, this cell wrll expenence
rn (b) during the period
compartment
to form one somite
regron of the embryo
into a caudal somrtrc domarn In whrch expression
(18h). This time Interval corresponds
rn the cell illustrated
the cell IS in the caudal
a clock lrnked to somitogenesis.
as a wave arrsing In a broad domarn from the posterior
It resides
to the formation 12 c-haryl
IS maintarned.
it ends gastrulation
waves C, Caudal;
rn a rostra1
S,, formrng
expressron of the c-hairy7
It
of presumptrve
R, rostal. (c) Oscillatrons
These oscillatrons
somrte; S,.
(Oh) untrl the moment
of 12 somrtes, whrch IS the number
in the PSM. At the 12th cycle, chary1
or turns ‘off’ If It is rn the rostra1 compartment.
cell of the PSM and define a clock linked to somite segmentation.
(1 h 30 mm), c-ha~y1
and progressing
of the c-hairy7
erther remarns ‘on’ If mRNA
occur
rn every
Somitogenesis
;lnal~sic
this
dispersion made
clock
at
the
single-ccl1
cxpcrinients
to
cell-~i~itonomo~is
11)
nication
in this
le\,cl
evalu;itc
txh3\
ccll-
tlllmu~l~
the
McGrew
and Pourquit+
491
Figure 4
contribution
ior and cell-cell
commw
D/l 1
pl-occss.
Notch 7
Notch2
RBP-Jk
Mew2
Molecular aspects of somitogenesis: role of the Notch-Delta pathway 01 cr clic past fen- yin, iii~di progress Iix Ix3m matic in the iinclci-~tandinfii~liii~ ofgcnctic
mechanisnis
guiding
somitogencsis
of ,q:ciic Imocl~-out cyxzrinicnt5 in the inousc. ‘liil)lc 1 lists wine of tlic IIIOIISC mutation5 n.liich gcncratcd o\wt dcfccts in somitogcncsis. Quite tinc\;pcctcdthi-oygh
II\C
the
Il. mice in \vhich the nc~irogcnic ,gcncs of the Notch-IkIt Gfpalliiig pcliway sidi as .\/INh/ [Al .-I?]. fMfN1 ]43’*], /?/I/‘,jh ]-l-l] orpmw/i/i/// [4.5”] ncrc linocked omit cdiil~it ;I strong 4c,qncii~;itioii I~hcnorvpe. I;igurc 4 ciiapan~s the csprcssion pttcrn
~cncs
of tlicsc
t‘c\\ ;Intcrior ~ariablc
somite\
sent hit
iiior~~~iologic~II
~:cnc\
lid \oniita
hit
.\ltcrnati\~cl~. wniitcs
might
somites not Ix
in thcsc
important
I-athcr for co-oi-dinatin~ 2 scpirarc
antcrioi-I!
the soniitic
Ic\xI.
and c\-hibit
the .\I’
;i\is
intri,qlin,ql~.
formed
Ix crw_hl
iqq this pith\\:I!
in defining
I\ hich
ii to Ix
‘l‘hc
[.i.i’].
Notch-I
klt:r
half-soniitc indcpcndcnt
pltll\\a)
idcntitics.
similar
injection
ofI\
to thcsc ild-t\
ucrc
ohraincd
or for
it
form;irion for cooi-dimtin,__ (r vmitc of :mtcrior and posterior soniitc
I
pttcrn
SCCIII~ to Ix 31ici t>)r tlic spcc-
rarhcr
CoiiiI);irtinCiiIs.
in .\j/lyW~.i
in \\hich
c (\\ IIci-c iiiolccw
pc oi- dominant-ncgati\
a process
of somitc
dots
morpho~:cncsis,
hi- modit~c~ition results in ;I doniinant loss of protein fuiiction) \ crsions of3 Iklta I~o~iiolo,~. S-c/d/c/Z. 0 r cf 3 .s~~/pmw of’h/i/h:u l~o~nolo, cr Icd to dimiption of iii\otoiii;il scgiiicnt~ltion. 5ufific\tin g 2 coiiwn ccl I-olc for this p:rrli\\ ;I\ in co-oi-tliixiting L crtclmtc son~ito~ciic~i~ [-I~~“~.
Iising cithci- n~\otomal OI- wIcrotoiii:iI ni:irkm rc\cdcd 2 rcsiclilal. alkit ii-i-qular. scgtncnral distril>rition: ho\\ c\ cl-. tlic .\I’ sulxli\~ision of tllc siCIcrotonic i\ found I0 1x1 p~-~~fou~icll~ affcctcd. (hiscc~ucntl~, the scgnicntxion of tlic pci-iphcr:ll iicr\ 011s system i\ ,~ w)sslv :ilmmiial. implicatmcsodcrni
was \Iio\\
wniitc
rccluired
of the pmxial
the IxiGc mctamci-ic
for cstal,lishing
ification
mutants
of
somltes.
cpithclial
pc.
iii thaw
PSM of
cpithc-
morl~‘hogcncsis.
21) corild Ix utiliscd to spwitj i-cdundanc~~ mighr rcscuc part of
aiial~~is
areas) in the mouse
suggest
for making their
(shaded
genes Important for somltogenesis. The knock-out many of which belong to the Notch-Delta pathway,
results In severe somltogenlc defects. The expression patterns of some of these genes define restricted domalns In the PSM and in the newly
is
padi\\
or gcnc
phcnoty
muLint
patterns
representative these genes,
mutants
of ~incoortlillatcci
thar thcw
hlorc
I,lit arc ~~ncoortlin~rtcd
Expresslon
:I
xnd pt-;~~ial nicsoclcrni i\ prc3nci tail soinircs arc wiually not ol~sm cd. ‘l’hc
in thcsc
trunk
prcwnrc
form
.\t ;I grch\
sks.
c~t~il~lishcd
I’SJI. In 211 thcsc inutaiih
in the
In\ OIL cinciiI of tlic Uotcli-I klt:i si,qii~rllin,g patliwa) in rcgLrlating scgincnt formation scciilh to Ix ;I clcir c;isc
fol-m&m
Ilot tllcrcfol-c
\,cCIll to
Table 1 Mouse knockouts displaying severe defects in somitogenesis. Gene targeted
Somltlc
phenotype
Reference
FGFRI
Expansion
Tbx6
CranIaI somltes
w/J t-3a
Loss of caudal
Notch 1
Irregtllar
Delta
Irregular somlte formatlon; segment polanty dlsrupted
1 fD111)
of axial mesoderm present somites;
somltes.
at the expense
but Irregular, paraxial tissue
basic metameric
of paraxial mesoderm;
remaIring
paraxlal mesoderm
may be replaced
pattern
establlshed;
basic metamerlc
pattern
[61
loss of all somite formatlon lost and replaced
by neuronal
tissue
by tissue segment
established;
WI polanty
disrupted;
somitlc
llneages
normal FGFRl
expresslon
141,421
are present; [43’1
Irregular somltes with Increasing seventy In posterior embryo; basic metameric pattern establlshed; somitic llneages are present; segment polanty disrupted; loss of Notch7 and D//l in PSM RBP-Ik
Irregular somltes; presence segment polarity dlsrupted
Mesp2
Irregular somlte formation; basic metamerlc pattern establlshed; somatic lineages segment polanty disrupted; loss of Notch7 and FGFRl expression
Param
No epithellal
somtte
c7.1
of dermomyotome
but metamerlc
and sclerotome
although
no myogenin
expresslon
[45’1 detected; [351
units are apparent;
somltlc
lineages
are present;
are present
[49’1 [501
492
Pattern
whcrc
formation
vcrtcbrates
Ixen
reported
and developmental
and
tly differ ;I role
to pIa)-
role for this signalling
mechanisms
since
in fly
these
gents
ha\xz
scgnientation.
not
:\ major
system in f~m.coiO/li/f~is in the control
of cell-fate choice in the lateral inhibition process u hich has lxcn u cll-descrihcd for the formation of the pcripheral ner\ 011sr);stem [47]. ‘I’hc defects in comite antero-postcrior
in Ketch-Iklta pathway mutants, suggests that the role of this path\\ a? in L erte-
specification
ho\ve\u-, I)rates
might
used,
be niorc
for instance.
wing
margin
related
in the
to boundar)
establishment
definition
of the
3s
Z~MJSO~A~/~~
[4X].
References and recommended
l
scription
factors
in
somitogenesis
rlcnionstratcd.
‘I’hese
;irc cxpresscd
3s ;i stripe
tlcrni
factors
(see Figure
has
include
in the
and the /M/~L/SIS gene
the I’Shl
which
of the trunk
soniitc
deri\xtiI~cs
proceeded
the
In conttxt
posterior
sclcrotonie
appears
Illllt;lllt
:\dditioixill~, is
lost
to
lac!i
the
the
I’S\1
in
lies upstruni
thcsc
of these
is
anterior
factors.
of
Gossler A, Hrabe de AngelIs M: Somitogenesis. 1998, 38:225-287.
3.
Catala M, Telllet MA, Le Douarln NM: Organization and development of the tail bud analyzed with the quail-chick chimaera system. Mech Dev 1995,51:51-65.
nor-
4.
Psychoyos D, Stern CD: Fates and migratory routes of primitive streak cells in the chick embryo. Development 1996, 122:1523-l
in \vhich
lacking.
this
coimpartnient.
niutants,
development.
2.
\vhilc
fairI)
and .\‘ot/fi/
of /+‘(;FR/
nicso-
pattern
knock-out,
conipartnicnt
txprcssion
from
hlcsp7
to the IId~~~/
Christ B, Ordahl CP: Early stages of chick somite Embryo/ fi3erl) 1995, 191:381-396.
Anat
Curr Top Dew B/o/
throughout
diffcrcntiation
[-We].
1.
\vhich
IIIOIISC knock-out
.l/~sp.! led to ;I disruption mally
IXXXI
presoniitic
is cxprcssed ‘I’he
of special interest * of outstanding Interest
tran-
recently
the .Uesp gcncs
rostra1
1) [-W”,SO].
of soniitic
l
I (basic hcli~-loop-helix)
role for b-HI,1
.A significant
reading
Papers of particular Interest, published wlthin the annual period of review have been highlighted as:
2nd AVofcfil
suggesting
SimilarlyT
that
the niilu-
534.
5. Richardson MK, Allen SP, Wright GM, Raynaud A, Hanken J: Somite . number and vertebrate evolution. Development 1998, 125:151-l 60. This review examines the variation ot somlte number between animal species. The authors propose that the process of somltogenesls shows a ‘dlssoclatlon’ from the ‘developmental hourglass’ model. 6.
Yamaguchl TP, Harpal K, Henkemeyer M, Rossant J: fgfr-1 is required for embryonic growth and mesodermal patterning during mouse gastrulation. Genes Dev 1994, 8:3032-3044.
rctainccl
7. .
Chapman DL, Papaloannou VE: Three neural tubes in mouse embryos with mutations in the T-box gene Tbx6. Nature 1998,
(see
This study demonstrates that Tbx6 IS necessary for the proper specification of the posterior paraxial mesoderm. The targeted mutation of Tbx6 resulted In the apparent conversIon of posterior paraxial mesoderm into neural-tube-like structures.
tion
of
the
somitc
p/u/.\ii
gene
forni~ition
hiit
rcsilltcd
in
paraxial
a complctc
niesodcrni
loss of
deri\ati\
cs
;I scgimcntal organisation [.50]. Kesults siicll as thcsc ha\,c lmnidecl c\,idencc that the process of soniitopicsis can he dissociated from wrtclxate segnicntation >llSO [I3.1,.
Conclusions ‘I’he
identification
tion
of the paraxial and
7%x6,
for
Notch-Iklta
of genes important mesodcrni
its
has pro\ iclcd insight togcncsis. point
into
Kcccnt
to the
Iq ~lIui/yl
iiiiportancc
nicdi:rtecl
studies
of both 11)
hy
the
and
of
the
gents
go\,crning on
sonii-
somitogcnesis
the autonomic
hclia\
internal
e\idcnced
an
clock
and to the role of cell-cell
oscillations
nications
lli/L?.d
as those
the mechanisms
molecular
cells as rcgiilatcd
of I’Shl
such
.Ilr~.sp:l,l./)N~~N\./.cand /Ioiy-like
pithway.
8. .
for Carla spccifica-
such ;is I~‘G/;KI,
segnientation
kotcll-l>clt:l
of somitc
and posterior
anterior clock icity of
could u hich
the
\1.hctllel-
brates
Ix
these
soniitic
translated ITin;illy.
path\\~a);s
in in\wtebratc
\\.hich
and
path-
generate
of soniitogencsis.
into it are
spxification
coniprtrments
will
the spatial be
conscrked
species scgnients
such
IO.
Marcelle C, Stark MR, Bronner-Fraser M: Coordinate actions of BMPs, Writs, Shh and noggin mediate patterning of the dorsal somite. Development 1997, 124:3955-3963.
11.
DIetrIch S, Schubert FR, Lumsden A: Control of dorsoventral pattern in the chick paraxial mesoderm. Development 1997. 124:3895-3908.
12.
Boryckl AG. Mendham L, Emerson C: Control of somite patterning by sonic hedgehog and its downstream signal response genes. Developmenf
1998,
125:777-790.
the
pcriod-
13.
Tajbakhsh S, Cossu G: Establishing myogenic identity during somitogenesis. Curr Opm Genet Dev 1997, 7:634~641.
14.
Tajbakhsh S, SpBrle R: Somite development: vertebrate body. Cell 1998, 92:9-l 6.
15.
Christ B, Schmidt C, Huang R. Wilting J, Brand-Saber1 B: Segmentation of the vertebrate body. Anat Embryo/ (Bedi 1998,197:1-8.
16.
Sander K: Specification of the basic body in insect embryogenesis. Adv insect Physol 1976, 12:125-238.
arrangenicnt
interesting in
Hlrsinger E, Duprez D, Jouve C, Malapert P, Cooke J, Pourqule 0: Noggin acts downstream of Wnt and Sonic Hedgehog to antagonize BMP4 in avian somite patterning. Development 1997, 124:4605-4614.
of
\\.hereas
g a tcniporril
9.
coiilmii-
signalling
in the
in\ ol\ cd in gencratin
is later
soniitcs. and
annclids cent
niorphogenesis
Yoshlkawa Y, Fullmorl T, McMahon AP, Takada S: Evidence that absence of Wnt-3a signaling promotes neuralization instead of paraxial mesoderm development in the mouse. Dev Biol 1997, 183~234.242. This report details the analysis of Wnt-3a mutant mice. Similar to the results shown above [7’1 with the Tbx6 knock-out, Wnf-3a mutant embryos do not correctly form paraxlal mesoderm; Instead an additional neural tube-llke structure IS generated medially.
ioiir
bay. ‘I’hc link Ixavccn these two systems has not yet hccn cstablishcd but it is rcasonahle to hypothcsizc that the clock ;Icts ripstrcani of the Ketch-lklta path\3xy. ksiilts from nioiisc: knock-out cxperinicnts strggcst that the latter system is iiiorc likely in\wl\d in the co-ordination
391:695-697.
other
to
xx
\wte-
as grasshopper
in a manner
rcniinis-
or
constructing
the
Somitogenesis
1 7.
Kornberg TB, Tabata T: Segmentation of the Drosophila Curr Opin Genet Dev 1993, 3:585-594.
18.
DeRobertls EM, Sasal Y: A common plan for dorsoventral patterning in Bilateria. Nafure 1996, 380:37-40.
19.
Muller M, von Welzsacker E, Campos-Ortega JA: Expression domains of a zebrafish homologue of the Drosophila pair-rule gene hairy correspond to primordia of alternating somites. Developmenf 1996, 122:2071-2078.
embryo.
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21. .
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