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A tale of tails
Christof Niehrs
Developing organisms still hold many surprises for biologists. For instance,
an entirely new ‘organizer’ — a clump of cells that tells other cells what to
do — has been discovered at a very early stage of zebrafish development.
he vertebrate tail is a somewhat
neglected organ. Protruding from the
rear, it does not, at first glance, seem
to serve much purpose other than to chase
off flies on cows and horses. In humans, the
rare atavistic occurrence of a rudimentary
tail can even be an embarrassment. Yet the
post-anal tail is one of the defining features
of chordates. In primitive chordates and
fish it promotes locomotion; lancelets use it
to burrow in sand; in mammals it stabilizes
posture and allows communication; and
monkeys also use it as a third leg. All vertebrates develop a tail as embryos, and
where the adults do without, it disappears
during fetal development or metamorphosis.
Despite its importance, however, we know
little about the molecular mechanisms that
underlie tail formation. On page 448 of this
issue, Agathon et al.1 present an analysis of
tail development in zebrafish. Unexpectedly,
they have discovered a new ‘tail-organizing
centre’ in early embryos, and have shown
that its molecular components include
some of the usual suspects.
The question of how the embryonic tail
forms is part of the greater problem of how
the main body axis — from head to trunk to
tail — is generated during early vertebrate
development. Of central importance for the
establishment of this body axis in amphibians is the upper dorsal blastopore lip, better
known as the Spemann organizer,which can,
after being transplanted into a different
embryo, cause a second body axis and hence
a twin embryo to form.Structures equivalent
to the amphibian organizer have been found
in all other vertebrates. The organizer produces signals that control the specialization
of nearby tissues; two of its main functions
are to induce the production and patterning
of neural tissue, and to cause ventral tissues
of the middle embryonic layer known as the
mesoderm to form dorsal tissues (such as
muscle)2.
Early transplantation experiments by
Otto Mangold3 showed that the Spemann
organizer can be subdivided into head,
trunk and tail organizers (Fig. 1a). So it
comes as a complete surprise that Agathon
et al.1 have discovered a tail-organizing
centre that appears to be independent of the
Spemann organizer. The authors carried out
experiments with zebrafish blastulae, early
embryos that consist of just a hollow ball of
cells. They took cells from the ventral margin
T
NATURE | VOL 424 | 24 JULY 2003 | www.nature.com/nature
a
Dorsal
b
Tail
Wnt
Head
BMP
Ventral
— a tissue that does not become part of the
‘shield’, considered to be the fish equivalent
of the Spemann organizer — and transplanted
the cells into host embryos. The result was
extra tails, consisting of donor- as well as
host-derived cells.Agathon et al. also showed
that inactivating the Spemann organizer did
not interfere with this ‘ectopic’ tail formation, implying that the two organizers are
indeed independent. The authors concede,
however, that the Spemann organizer is
required for ‘proper’ tail formation, as the
ectopic tails were incomplete: for instance,
they lacked the stiff supporting rod known as
the notochord, which is derived from the
Spemann organizer.
The authors also established that this tailorganizer activity involved growth-factor
proteins of the Wnt, bone morphogenetic
protein (BMP) and Nodal families. These
signalling molecules were good candidates
for such a role because they are known to be
present in the ventral margin, and interfering with the signalling pathways to which
they contribute inhibits tail formation.
Agathon et al. now show that misexpressing
these growth factors in combinations, but
not singly, leads to the generation of extra
tails — which are, again, incomplete. So
all three growth factors are involved in
© 2003 Nature Publishing Group
Figure 1 Organizers of development. a, The
Spemann organizer. Otto Mangold3 took
different segments from the Spemann organizer
of early newt embryos (neurula stage; left), and
transplanted them into the fluid-filled cavity
of embryos at the even earlier gastrula stage
(centre). As tadpoles (right), the embryos
displayed duplicate, region-specific balancers
(stabilizing threads in the head), heads, trunks
or tails. (Modified from ref. 10.) b, Doublegradient model for generation of the body axes,
showing how perpendicular activity gradients
of Wnts and bone morphogenetic proteins
(BMPs) regulate head-to-tail and dorsal–ventral
patterning. The gradients are indicated by
colour scales; arrows indicate spreading of the
signals. Patterning begins at gastrula stages, but
for clarity is depicted in an early amphibian
neurula. The formation of head, trunk and tail
requires increasing Wnt activity. Agathon et al.1
have found that tails develop where high levels
of BMP and Wnt signals intersect, towards the
posterior. (The model is adapted from ref. 9 and
is a molecular interpretation of the classical
double-gradient theories reviewed in ref. 11.)
the newly discovered tail-organizer activity.
The wider significance of these findings
concerns how they relate to existing models
for region-specific organizers, in which
Wnts, BMPs and Nodals are no strangers.
The head- and trunk-organizing activities of
the Spemann organizer are known to require
combinations of these three types of growth
factor4. Head-organizer activity requires
inhibition of all three signals; trunk formation requires Nodal signalling to be active
but BMP signalling to be inhibited; and we
now know that the tail organizer requires
signalling by all three factors. The drawback
of previous organizer models was that they
failed to explain the difference between the
trunk and tail organizers in molecular terms,
except for tail development at later stages5,6.
Thanks to Agathon et al., this riddle seems
well on the way to being solved.
A few issues remain, however. First,
Agathon and colleagues’ model1 emphasizes
qualitative differences in combinatorial
signalling, with key signals being either ‘on’
or ‘off ’ — and this is enough to explain the
phenomenon of discrete organizers as they
have been observed in transplantation
experiments for the past 75 years. For
instance, the authors propose that Wnt
signalling needs to be ‘on’ to generate the tail,
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news and views
but ‘off ’ to produce the trunk. Yet we know
that all three growth factors act in a concentration-dependent fashion during early axis
formation. A gradient of Nodal protein
instructs cells at different points along the
gradient to take on different mesodermal
fates; this then translates into an increasing
dorsal-to-ventral gradient of BMP7,8 and an
increasing head-to-tail gradient of Wnt9,
generating a continuum of positional information. Completely blocking Wnt inhibits
trunk formation, so trunk-organizer activity
must require some — probably low levels of
— Wnt signalling, rather than the complete
inhibition suggested by the authors.
Second, unlike BMPs and Wnts, Nodal
proteins affect the head-to-tail patterning
of neural tissue only indirectly, inducing
mesendodermal tissue to produce, for
instance, Wnts, Wnt inhibitors and BMP
inhibitors at different threshold activities of
Nodal. A model complementary to that of
Agathon et al. focuses on the more direct
players — BMP and Wnt — in regulating
axis formation (Fig. 1b), and takes into
account their activity gradients.
Finally, how does the tail organizer
uncovered by Agathon et al. interact with the
Spemann organizer to induce complete tails?
And how can we integrate the process of
trunk ‘segmentation’, which is controlled
from the tail bud? Whatever the answers, the
new work1 should generate greater interest in
questions relating to the tail.
■
Christof Niehrs is in the Division of Molecular
Embryology, Deutsches Krebsforschungszentrum,
Im Neuenheimer Feld 280, 69120 Heidelberg,
Germany.
e-mail: niehrs@dkfz-heidelberg.de
1. Agathon, A., Thisse, C. & Thisse, B. Nature 424, 448–452
(2003).
2. Harland, R. M. & Gerhart, J. Annu. Rev. Dev. Biol. 13, 611–667
(1997).
3. Mangold, O. Naturwissenschaften 21, 761–766 (1933).
4. Piccolo, S. et al. Nature 397, 707–710 (1999).
5. Beck, C. W. & Slack, J. M. Development 126, 1611–1620 (1999).
6. Beck, C. W., Whitman, M. & Slack, J. M. Dev. Biol. 238, 303–314
(2001).
7. De Robertis, E. M., Larrain, J., Oelgeschlager, M. & Wessely, O.
Nature Rev. Genet. 1, 171–181 (2000).
8. Schier, A. F. Curr. Opin. Genet. Dev. 11, 393–404 (2001).
9. Kiecker, C. & Niehrs, C. Development 128, 4189–4201 (2001).
10. Gilbert, S. F. Developmental Biology 7th edn (Sinauer,
Sunderland, Massachusetts, 2000).
11. Gilbert, S. F. & Saxen, L. Mech. Dev. 41, 73–89 (1993).
Quarks
Up/
anti-up
Down/
anti-down
Charm
Strange
Top
Bottom
Baryon
Meson
K+
Proton
Deuteron
Proton
New meson?
Neutron
New baryon?
Particle physics
Strange days
Frank Close
Three new subatomic particles have been found, and all survive for an
unusually long time before they decay. Physicists now face the
challenge of explaining this within the framework of the existing theory.
t is as if Cleopatra had fallen from
her barge in BC and had not yet hit
the water.” Such was the description
half a century ago of the discovery of the
astonishingly long lifetime (up to about
1018 seconds) of strange particles. Everyday
matter, such as protons and neutrons, is
made of two types of quark, known as ‘up’
and ‘down’ (Fig. 1). But in 1947, new particles were discovered that contained a third
type of quark, called ‘strange’1. Today,
strange particles are a well-established part
of the standard model of particle physics,
which now includes six types of quark. We
know that their seemingly long lifetimes are
a consequence of the ‘weak’ interaction that
they undergo in decaying: if instead they
were subject to the powerful ‘strong’ interaction their lives would be over in around
10123 seconds. Instead, death by decay is
neutered by the presence of strangeness.
In the past two months, three different
particles have been discovered, and explaining them has proved a challenge for theorists.
Although not as extreme as the above example, each of these new particles has an unusually elongated lifetime. Two of them are
‘mesons’, each containing a strange antiquark and a charm quark (the fourth quark
“I
376
type)2,3. The reason for their metastability is
understood, but their detailed nature and
dynamics remain to be resolved. The third
particle4 is a member of the ‘baryon’family of
particles that also includes the proton and
neutron.But,unlike the proton and neutron,
this particle has some strange-quark content. In fact, unlike any other baryon known,
it has overall one unit of ‘positive strangeness’. It is an enigma. The quark model that
now underpins the standard model was
developed, in part, under the assumption
that such things do not exist.And although it
may be possible to interpret this particle as a
combination of four quarks (two up, two
down) and a strange anti-quark (providing
that unit of positive strangeness), the challenge is to explain also why this ‘pentaquark’
does not fall apart more quickly.
Viewed at high resolution (through highenergy particle collisions), mesons and
baryons appear to be swarms of quarks, antiquarks and gluons — the quantum bundles
that glue these constituents to one another,
according to the theory of quantum chromodynamics (QCD). At lower resolution, the
picture is simpler. The mesons and baryons
form two distinct classes: mesons consist of a
single quark and anti-quark; baryons seem
© 2003 Nature Publishing Group
Figure 1 Quarks and particles. In the standard
model of particle physics, there are six quarks —
fundamental particles that are the buildingblocks of many others. Each quark also has an
anti-matter partner, an anti-quark. Pairings of
quarks and anti-quarks form ‘mesons’, such as the
K & ; three quarks form ‘baryons’, such as the
proton. The picture builds up further: a threequark proton and a three-quark neutron together
form a deuteron; adding more protons and
neutrons — more three-quark combinations —
builds up atomic nuclei. The discoveries of what
seem to be a new meson2,3 and a new baryon4
don’t easily fit the established picture. The new
meson may in fact be a ‘molecule’ of two mesons,
and the baryon might be a ‘pentaquark’ state.
to be formed from just three quarks. In addition, QCD seems to allow more complicated
clusters of quarks or anti-quarks — atomic
nuclei are familiar examples of quarks bound
in multiples of three. An open question is
whether there are analogues containing antiquarks. The simplest would be two quarks
balanced by two anti-quarks, in effect a ‘molecule’ of two conventional mesons, or three
quarks accompanied by an additional quark
and an anti-quark,making a pentaquark.
Unambiguous evidence for such states in
the data is lacking. Their absence is attributed to the ease with which they would fall
apart into a pair of conventional mesons,or a
meson and a baryon. It is estimated that they
would survive for less than 10124 seconds,
which is at the current limit of detection.
But the sightings of the three metastable
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