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Evolution of the bilaterian mouth and anus

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DOI: 10.1038/s41559-018-0641-0

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 Review Article
https://doi.org/10.1038/s41559-018-0641-0

Evolution of the bilaterian mouth and anus

Claus Nielsen   1,4*, Thibaut Brunet   2,3,4* and Detlev Arendt   2,4*

It is widely held that the bilaterian tubular gut with mouth and anus evolved from a simple gut with one major gastric opening.
However, there is no consensus on how this happened. Did the single gastric opening evolve into a mouth, with the anus forming
elsewhere in the body (protostomy), or did it evolve into an anus, with the mouth forming elsewhere (deuterostomy), or did it
evolve into both mouth and anus (amphistomy)? These questions are addressed by the comparison of developmental fates of
the blastopore, the opening of the embryonic gut, in diverse animals that live today. Here we review comparative data on the
identity and fate of blastoporal tissue, investigate how the formation of the through-gut relates to the major body axes, and
discuss to what extent evolutionary scenarios are consistent with these data. Available evidence indicates that stem bilaterians
had a slit-like gastric opening that was partially closed in subsequent evolution, leaving open the anus and most likely also the
mouth, which would favour amphistomy. We discuss remaining difficulties, and outline directions for future research.

T
he origin of bilaterian body plans, with through-gut, mouth
and anus, is a central topic in animal evolution. In 1908, Karl
Grobben1 proposed to divide the Bilateria into Protostomia
and Deuterostomia, based on observed differences in the devel-
opmental fate of the blastopore (the single external opening of the
cup-shaped, bilayered gastrula; Fig. 1a). In Protostomia, the blasto-
pore had been observed to develop into the mouth, with the anus
forming secondarily (‘protostomy’, or ‘mouth first’), whereas in
Deuterostomia, it developed into the anus, with the mouth form-
ing secondarily (‘deuterostomy’, or ‘mouth second’). Following
Haeckel’s biogenetic law2, Grobben interpreted these developmental
differences as vestiges of divergent evolutionary paths. Both groups
were assumed to have evolved from a cup-shaped ancestor with a
single gastric opening, called gastraea3. He proposed that this open-
ing had evolved into the mouth in Protostomia, and into the anus in
Deuterostomia. Grobben’s original evolutionary scenario is shown
as option 1 in Fig. 1b.
Even though Grobben’s subdivision into Protostomia and
Deuterostomia has, with some adjustments, survived into the
molecular age4–8, his evolutionary scenario has been rejected for
several reasons. First, it suggests that the anterior–posterior axes of
Protostomia and Deuterostomia are not the same, which is incon-
sistent with the collinear expression of Hox genes along the ante-
rior–posterior axes in both groups9,10. Second, it assumes that the
mouth in Protostomia and Deuterostomia are not homologous (and
neither are the anuses); however, there is ample evidence to the con-
trary, notably from the expression of conserved markers9,11–13 (with
the exception of the chordate mouth14). Third, several taxa with
clear deuterostomy have been discovered in Protostomia, or moved
to the Protostomia, such as the chaetognaths4.
Several alternative perspectives have since arisen to explain the
evolution of mouth, anus, through-gut, and of the major body axes,
from the comparative study of development. Here, we discuss these
different interpretations and challenge their supporting evidence.
For this, it is important to distinguish the developmental processes
and stages that are observed in extant animals from the inferred evo-
lutionary ancestors and their transformations, which occurred hun-
dreds of millions of years ago. For example, ‘gastrula’ and ‘blastopore’
are developmental terms, whereas ‘gastraea’ and ‘gastric opening’
refer here to the ancient body plan of adult evolutionary ancestors.
To avoid confusion, we will thus refer to the observed developmen-
tal processes of blastopore closure as developmental protostomy or
deuterostomy, and to the assumed evolutionary transformations of
the gastric opening in hypothetical ancestors as ‘evolutionary pro-
tostomy or deuterostomy’ (evo-protostomy or evo-deuterostomy).
A plurality of views
For the past decades, there has been an intensed debate on the con-
flicting hypotheses of how bilaterian ancestors might have evolved
a mouth and anus9,15–18 (Fig. 1b,c). As a starting point, these hypoth-
eses posit that early metazoans had a gastric cavity with one major
gastric opening for food intake and defecation3,12,18–21. This notion
is strongly supported by the occurrence of such a cup-shaped body
plan in cnidarians and ctenophores22. Opinions differ on how, and
when, the one gastric opening evolved into a separate mouth and/
or anus, connected by a through-gut. This is clear from the differ-
ent interpretations of what the cnidarian–bilaterian ancestor (CBA)
and the protostomian–deuterostomian ancestor (PDA) might have
looked like, and how they gave rise to the last protostomian and
deuterostomian common ancestors (Fig. 1b,c).
In the first set of interpretations, which are shown in Fig. 1b,
the ancestor with one gastric opening is tipped over, so that the
ancient gastric opening becomes the new mouth (evo-protos-
tomy)18,21,23 or the new anus (evo-deuterostomy)24,25. The second
opening is newly acquired or persists from smaller openings at the
apical pole of the animal, unrelated to the former gastric open-
ing. These two solutions correspond to the divergent paths that
Grobben had proposed for early Protostomia and Deuterostomia
(option 1). Alternatively, evo-protostomy and evo-deuterostomy
have also been suggested to have occurred — the one or the other
— in the bilaterian stem, leading to a protostomous PDA (option
2) or to a deuterostomous PDA (option 3). These options have
in common that they derive the anterior–posterior axis of the
PDA from the primary axis of the CBA — however, in reverse
orientations in option 2 versus option 3. Consistent with this,
cnidarians26,27 and ctenophores21 form pore(s) at their aboral end,

Biosystematics, The Natural History Museum of Denmark, University of Copenhagen, Copenhagen, Denmark. 2European Molecular Biology Laboratory,
1

Developmental Biology Unit, Heidelberg, Germany. 3Present address: Department of Molecular and Cell Biology, Howard Hughes Medical Institute,
University of California, Berkeley, Berkeley, CA, USA. 4These authors contributed equally: Claus Nielsen, Thibaut Brunet, Detlev Arendt. *e-mail: cnielsen@
snm.ku.dk; t.brunet@berkeley.edu; arendt@embl.de

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a b A

Evo-protostomy P
*

Gastrula

Protostomy Deuterostomy A

Evo-deuterostomy
* P
Mouth

Mouth Mouth 1 Grobben’s scenario 2 Protostomous PDA 3 Deuterostomous PDA

LPA PDA
‘Urmund’
PDA CBA CBA
(limit between
LDA PDA
stomodaeum
and midgut)

c A

Gill slit
P
Evo-amphistomy
Midgut Midgut Midgut
A

Evo-protostomy *
P
‘Umund’
(anus) Evo-schistostomy

Evo-deuterostomy
*
*
A P
*

4 Amphistomous PDA 5 Protostomous PDA 6 Deuterostomous PDA 7 Schistostomous PDA

Anus ‘Umund’ PDA LPA
(anus) CBA CBA PDA CBA PDA
PDA LDA
Annelid Enteropneust Chaetognath

Fig. 1 | Theories for the evolutionary origin of mouth and anus in the bilaterians. a, Grobben’s observations of two types of developmental fate of the
blastopore. b, Evolutionary scenarios that derive the bilaterian anterior–posterior axis from the primary axis of a gastraea-like ancestor. The circular gastric
opening evolves into mouth or anus. c, Evolutionary scenarios that derive the bilaterian anterior–posterior axis from the secondary (directive) axis of a
gastraea-like ancestor. The slit-shaped gastric opening evolves into mouth and/or anus. Each scenario is represented by one grey box, with its specific
interpretation and labelling of the depicted ancestors. A, anterior; LDA, last common deuterostomian ancestor; LPA, last common protostomian ancestor;
P, posterior. Asterisks indicate new openings that have formed independently of the blastopore and represent either new mouths or new anuses. Panel a
adapted from ref. 1, Kaiserlich-Königliche Zoologisch-Botanische Gesellschaft in Wien.

unrelated to the main gastric opening, which might relate to the
presumed secondary opening at the apical pole.
The second set of interpretations, which are shown in Fig. 1c,
have in common that the bilaterian mouth and/or anus derived
from a slit-like gastric opening. We refer to the formation of a
slit-shaped gastric opening as ‘schistostomy’ (slit-shaped mouth).
Supporting evo-schistostomy, the gastric opening takes the shape of
a slit in anthozoan cnidarians28; and a slit-like gastric opening has
often been seen as the first step towards bilateral symmetry22,29,30.
Evo-schistostomy scenarios derive the anterior–posterior axis of
Protostomia and Deuterostomia from the secondary body axis of
a gastraea-like ancestor alongside the gastric slit (which would cor-
respond, for example, to the directive axis of cnidarians). These
options differ however in the presumed fate of the gastric slit, which
is illustrated in options 4–7. Sedgwick29 was the first to suggest that
both mouth and anus derived from the gastric slit, through the
fusion of the lateral lips, which is referred to as amphistomy (opening
at both sides) in the literature (evo-amphistomy) and corresponds
to option 4. Alternatively, the gastric slit might have closed from
posterior to anterior until only the mouth was left, or from ante-
rior to posterior until only the anus was left, with the second open-
ing — anus or mouth, respectively — forming independent of the
initial gastric slit. Options 5 and 6 represent these interpretations,
starting from a CBA with a slit-like gastric opening and evolving
via evo-protostomy or evo-deuterostomy, respectively, into a pro-
tostomous or deuterostomous PDA. Finally, yet another scenario is
possible, namely that the gastric slit remained open in the PDA, to
then close independently in the lineages leading to Protostomia and
Deuterostomia (option 7). Similar to Grobben’s proposal, this would
indicate independent evolution of the through-gut in Protostomia
and Deuterostomia. In contrast to Grobben’s initial scenario, it sug-
gests homology of the anterior–posterior axes between Protostomia
and Deuterostomia and this would thus be consistent with the con-
served expression of hox genes (in Protostomia, Deuterstomia and
Cnidaria, see ‘Comparison of body axes in bilaterians and cnidar-
ians’ below).
Comparison of body axes in bilaterians and cnidarians
How can we test these possibilities? Clearly, they differ in their pre-
dictions how the body axes of living descendants should compare.
To challenge this, we can compare the activity of Hox genes, which
are involved in axial patterning31, and the activity of Wnt and BMP
signals, which are known to span a conserved Cartesian coordinate
system in bilaterians32 and cnidarians33,34, as illustrated in Fig. 2.

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Review Article NATure Ecology & EvoluTIon

a Cnidarian Annelid Chordate

D V
m

A P A P

Primary axis D
V

b D
m
V

P P

bl V D

Directive axis BMP Wnt1 Wnt4

Fig. 2 | Two conflicting possibilities of how the body axes in cnidarians and bilaterians are related, based on different interpretations of axial Hox,
canonical Wnt and Bmp activity. a, The primary axis of cnidarians corresponds to the bilaterian anterior–posterior axis. b, The secondary (directive) axis
of the cnidarians corresponds to the bilaterian anterior–posterior axis. a,b, Pink, conserved apical tissue as defined by conserved gene expression22. Double
arrow, collinear Hox gene expression and activity. Red dots and arrows, Bmp expression and activity. Dark- and light-blue dots and arrows, Wnt1 and Wnt4
expression and activity22. Black dashed line, the extent of blastoporal tissue. a, Grey dashed line, secondarily enlarged extent blastoporal tissue according
to this interpretation.

Figure 2a shows a representative cnidarian, annelid and chor-
date in an orientation that aligns the bilaterian anterior–posterior
axis with the cnidarian primary axis. The suggested homology
between the bilaterian anterior–posterior and cnidarian primary
axes would be consistent with options 1–3 in Fig. 1b, and would
predict differential Hox activity along the cnidarian primary axis.
Indeed, this has been suggested based on an analysis of Hox gene
expression in the sea anemone35. Similarly, Wnt signals pattern the
primary body axis of cnidarians33,36,37 and BMP pattern their direc-
tive axis38 — so that the orientation of Wnt and BMP signals in
developing sea anemones matches the orientation in a developing
chordate (Fig. 2a). However, the seemingly simple alignment of the
bilaterian anterior–posterior and cnidarian primary axes produces
a conflict between the Hox and the Wnt data regarding the orienta-
tion of the primary axis compared to the anterior–posterior axis.
Notably, the sea anemone expresses a ‘posterior’, hox9-13-related
gene at its aboral pole, which would thus correspond to bilaterian
‘posterior’, in line with evo-protostomy35,39 (option 2 in Fig. 1b).
By contrast, the oral activity of cnidarian canonical wnt genes is
similar to posterior activity in bilaterians32 and instead supports
evo-deuterostomy (option 3 in Fig. 1b). Because the orientation
of the Wnt axis encompasses multiple Wnt signals and antagonists
(whereas the above interpretation of the Hox axis35 relies on the
expression of one gene only), option 3 with evo-deuterostomy is
more plausible. Clearly, option 2 with evo-protostomy should be
discarded as it is in conflict with the Wnt data.
By contrast, Fig. 2b aligns the cnidarian secondary axis, called
the directive axis, with the annelid and chordate anterior–posterior
axis. This is in line with all of the scenarios in Fig. 1c (options 4–7)
and with a re-analysis of the Nematostella Hox expression data that
uncovered a pronounced pattern of staggered collinear expression
of Nematostella Hox genes parallel to the blastoporal slit, patterning
the gastric pouches along the directive axis38,40 (Supplementary Fig.
1). These data make the cnidarian directive axis a much stronger
candidate for the ‘true’ collinear Hox axis of the animal38,40,41. Under
this hypothesis, axial patterning in the sea anemone compares well
to that in an annelid worm, and also aligns with the development
of a frog (Fig. 2b) — taking into account that Wnt signalling in
chordates is active not only along the anterior–posterior but also
along the dorsal–ventral axis42,43, and that BMP is also active pos-
teriorly in the frog gastrula44. It is, however, important to note that,
although the shared collinear hox pattern clearly supports homol-
ogy between the cnidarian directive axis and the bilaterian ante-
rior–posterior axis, the orthology of individual hox genes between
cnidarians and bilaterians remains incompletely resolved45,46, indi-
cating that both Hox clusters might have undergone some degree
of independent expansion from an ancestral complement of a
minimum of two Hox genes.
In summary, the comparison of body axes in cnidarians and
bilaterians appears to be consistent with option 3 in Fig. 1b (evo-
deuterostomy), however it more strongly supports all of the options
shown in Fig. 1c.
Comparison of blastoporal fates
Besides axial relationships, the developmental comparison of blas-
toporal fates remains a valid approach to test the different scenarios
(Fig. 1). Supporting this developmental–evolutionary link, in today’s
cnidarians and ctenophores22, the single gastric opening develops
directly from the blastopore, which suggests that this was also the
case in the bilaterian stem line. If so, any evolutionary derivative of
the gastric opening in today’s bilaterians should also develop from
the blastopore — at least ancestrally.
To address this, classical comparisons have focused on the fate of
the actual blastoporal opening (Supplementary Table 1), looking for
direct continuity with the mouth and/or anus. This is illustrated by
red lines in Fig. 3. In light of these data, it should be stressed that an
overt amphistomous pattern with the blastoporal opening directly
giving rise to both mouth and anus is very rare. First, it has only
been reported in few Protostomia, such as the annelid Podarke47, the
nematode Pontonema48 (Fig. 3a,b), and in Onychophora, species of
which have an early and unique mouth–anus furrow that splits into
mouth and anus (although whether the onychophoran mouth–anus
furrow should be called a ‘blastopore’ is disputed49; Supplementary
Information). Second, only few cases exist in extant Protostomia
in which the open blastopore turns into only a mouth as predicted
by the original definition of protostomy. This is seen, for example,

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NATure Ecology & EvoluTIon Review Article
a Podarke b Pontonema c Polygordius d Crepidula e Capitella

s/m

s/m

p/a

s/m f Neochildia s/m p

j Peripatopsis k Tenebrio
m s
s

p/a
g

g Viviparus h Enteropneust i Novocrania me

Fig. 3 | Fates of the blastoporal opening and of the periblastoporal tissue. The blastopore lips are indicated in red and fused blastopore lips are shown
as dashed red lines; a new anus is indicated by a yellow asterisk and a new mouth by a yellow circle. a,b, The blastoporal opening divides into mouth and
anus (amphistomy sensu stricto). a, The annelid Podarke. b, The nematode Pontonema. c, The annelid Polygordius. The blastopore divides into mouth and
a posterior opening, which closes, and a new anus subsequently develops in the same area. Only the central part of the vental side is drawn. d,e, The
blastopore closes from behind in a zipper-like manner. d, The gastropod Crepidula. e, The annelid Capitella, which has epiboly and in which the 2d cell
(the somatoblast) spreads over the whole posttrochal region, fusing in the ventral midline and leaving a ring of cells from the third micromere quartet
in the stomodaeum and around the anus. f, The acoel Neochildia. The ‘blastopore’ becomes the mouth, and fate mapping16 indicates the presence of
periblastoporal tissue along the ventral midline; as micromeres 3a and 3b, which become ventral ectoderm, directly border the endodermal macromeres
3A and 3B and thus represent blastoporal tissue according to a previously published definition60. This is consistent with a study in which live imaging in
another acoel found that the 3a and 3b micromeres border the closing blastopore16. g,h, The blastopore becomes the anus. g, The gastropod Viviparus.
h, Tornaria larva of an enteropneust. i. The blastopore closes and the mouth and anus are formed anew in the brachiopod Novocrania. j,k, Species with
a blastoderm. j, The onychophoran Peripatopsis. The ‘blastopore edge’ surrounds stomodaeum, proctodaeum, a midventral zone with exposed yolk and
the lateral endoderm (midgut) rudiments (based on ref. 506). k, The insect Tenebrio. a, anus; g, gonopore; m, mouth; me, mesoderm; p, proctodaeum; p/a,
proctodaeum/anus; s, stomodaeum; s/m, stomodaeum/mouth. In species with spiral cleavage the blastomere quartets are indicated. Orange, second
quartet; green, third quartet; blue, forth quartet; brown, endoderm. Adapted from ref. 47, Wiley (a); ref. 48, Russian Society of Nematologists (b); ref. 68,
Springer (c); ref. 60, BMC (d); ref. 507, BMC (e); ref. 115, Elsevier (f); ref. 52, G. Fischer (g); ref. 61, Linnean Society of New South Wales (k).

in some molluscs50,51, nemerteans with pilidium larvae and bryo-
zoans with cyphonautes larvae (Supplementary Information). In
almost all other reported cases of developmental protostomy in
Protostomia, a slit-like blastoporal opening closes from behind by
lateral fusion of the posterior parts of the blastoporal lips, leaving
open only the anterior mouth opening (Fig. 3c–e); the anus then
develops at the posterior end of the fused blastopore lips. These may
represent cases of derived amphistomy with partial and temporary
closure of the blastoporal opening. Third, the blastoporal open-
ing directly becomes the anal opening in almost all Deuterostomia
(Fig. 3h) and in several protostomian lineages, not only in small,
restricted clades (genera or families), such as the snail Viviparus52
(Fig. 3g), the annelid Eunice53, the nemertean Tetrastemma20,54 and
the crustaceans Penaeus and Sicyonia55,56, but also in whole phyla,
such as priapulids17 and chaetognaths57. The isolated occurrence of
developmental deuterostomy in Eunice and Viviparus, which are in
phyla with an overall non-deuterostomous gastrulation, indicates a
considerable degree of plasticity in the fate of the actual blastoporal
opening, even between closely related lineages.
Notably, many animal groups gastrulate without any blas-
toporal opening so that both mouth and anus form secondarily
(Supplementary Table 1). In these cases, large amounts of yolk
in the vegetal blastomeres prevent the formation of a gastrocoel,
leading to the type of gastrulation called epiboly58,59. In these cases,

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Review Article
the blastopore is no longer a true pore, and the blastoporal lips no
longer enclose a lumen but enclose the boundary between ecto-
dermal and endomesodermal tissue instead60. Epiboly is observed
in many annelids, such as Platynereis and Capitella (Fig. 3e), and
in most insects61.
Therefore, the fate of the actual blastoporal opening appears
to be an unreliable character for classifying and reconstruct-
ing ancestral gastrulation patterns, as it changes repeatedly and
rapidly in evolution62, for example, concomitant with changes in
yolk content.
Focus on circumblastoporal tissue
Even if the blastoporal opening is lost in evolution (for example,
owing to epiboly), the tissue surrounding the internalizing endome-
sodermal cells will still give rise to oral and/or anal tissue (with sto-
modaeum and proctodaeum)63, and thus remain informative about
the ancestral blastoporal fate. We define blastoporal tissue as the
ectodermal cells that are initially in contact with the internalizing
endomesoderm, as well as the immediate endomesodermal neigh-
bours of these cells, building on a previously proposed definition60.
Under this definition, a cell remains blastoporal even if it moves
away from the blastopore during blastopore closure. Notably, com-
parative developmental data indicate that the fate of the blastoporal
tissue is indeed less prone to evolutionary change than the fate of
the actual blastoporal opening. For example, during amphibian gas-
trulation the blastoporal opening directly becomes the anus in some
species, whereas it closes in others with the anus reopening later in
the same position64,65. Still, the amphibian anal cells always develop
from blastoporal cells and their gastrulation classifies as deuteros-
tomous — regardless of the transient closure of the actual opening.
In line with other studies60,66,67, we thus consider the fate of the tis-
sue surrounding the blastopore (rather than its actual opening) the
most relevant defining criterion for proto-, deutero- or amphisto-
mous gastrulation patterns.
Owing to its evolutionary stability, the fate of the blastoporal tis-
sue (unlike the fate of the blastoporal opening) can be used to test
the evolutionary scenarios in Fig. 1b,c. Specifically, the scenarios in
Fig. 1b predict blastoporal tissue to give rise to mouth tissue only
(option 2; Supplementary Fig. 5a), or anal tissue only (option 3;
Supplementary Fig. 5b) — but not both. By contrast, the scenarios
in Fig. 1c, which derive mouth and/or anus from a gastric slit, com-
monly predict blastoporal tissue to give rise to midline tissue that
forms alongside the closing blastoporal slit. They differ, however, in
their predictions regarding mouth and anal tissue. Only in the case
of evo-amphistomy would both mouth and anal tissue arise from
blastoporal tissue — in addition to, and at opposite ends of, the
midline tissue (option 4; Supplementary Fig. 5c). Evo-protostomy
would instead derive midline plus mouth (option 5; Supplementary
Fig. 5d), and evo-deuterostomy derives midline plus anal tissue
from the blastoporal tissue (option 6; Supplementary Fig. 5e). How
do these predictions relate to observed blastoporal tissue fates?
Amphistomy and deuterostomy across Protostomia
For Protostomia, the focus on blastoporal tissue fates strongly
impacts on our classification of gastrulation patterns as proto-,
deutero- or amphistomous. Notably, the last decades have seen a
plethora of studies in different animal models focusing on the
movements, molecular identity and fate of blastoporal tissue. One
efficient way to determine blastoporal fates is through lineage trac-
ing, which has been done in various Protostomia47,60,68. Figure 3a–k
summarizes lineaging data for five phyla, showing a clear consen-
sus: in each case, circumblastoporal tissue gives rise to oral and anal
tissue, and to ventral midline tissue, which connects the two. For
example, lineage studies in the annelid Polygordius have revealed
that cells that form the later mouth, anal and ventral midline tis-
sue derive from the second, third and fourth micromere quartets
1362 Nature EcoloGy & Evolution | VOL 2 | SEPTEMBER 2018 | 1358–1376 | www.nature.com/natecolevol
NATure Ecology & EvoluTIon
surrounding the blastopore (Fig. 3c). (Note that, besides blastoporal
cells, the early ventral midline additionally incorporates some more
lateral cells by a process of mediolateral intercalation.) Assuming
reliability of these observations, we propose to reclassify gastrula-
tion in these animals as amphistomous. Similarly, in a more recent
study69 on gastrulation and fate of the blastoporal tissue in the slip-
per snail Crepidula fornicata, it was shown that cells that later form
mouth (3a, 3b), midline (3c, 3d) and anal tissue (2d) initially abut
the blastopore. These observations are consistent with develop-
mental amphistomy (even if gastrulation is epibolic and no actual
blastoporal opening is observed). The same is true for gastrula-
tion in phoronids, in the brachiopod Terebratalia and in the classi-
cal model systems Caenorhabditis and Drosophila (Supplementary
Information, Supplementary Fig. 4).
Does this mean ancestral Protostomia were amphistomous? Not
quite, given the remarkable occurrence of developmental deuteros-
tomy in some important Protostomia taxa, for example, in chaeto-
gnaths and priapulids. For these groups, it is clear that blastoporal
tissue gives rise to anal tissue, without any known contribution to
mouth tissue. This leaves us with conflicting evidence regarding the
ancestral fate of blastoporal tissue in Protostomia, Deuterostomia
and Bilateria. Using the revised definition of amphistomy, and map-
ping the distribution of proto-, deutero- and amphistomy onto
a bilaterian tree (see Supplementary Information and previously
published studies70–477), deuterostomy and amphistomy appear to be
nearly equally parsimonious ancestral states of the blastoporal tis-
sue for Protostomia, Deuterostomia and Bilateria (Fig. 4).
From these results, we can safely conclude that protostomy is
not ancestral — neither for Protostomia nor for Bilateria — thus
refuting evo-protostomy (options 2 and 5 in Fig. 1). However, the
different variants of evo-deuterostomy and evo-amphistomy remain
plausible options. How can we progress further?
Evo-amphistomy or evo-deuterostomy?
The central question is whether amphistomy or deuterostomy is
ancestral for Protostomia, Deuterostomia or Bilateria. The specific
expression of conserved transcription factors demarcating blasto-
poral tissue has been established as another good proxy for blasto-
poral tissue fates. For example, brachyury and foxA demarcate the
entire blastopore in almost all studied animals, and other factors
specify the anterior versus posterior part of the blastoporal tissue.
In cnidarians, these factors are expressed around the blastopore
during gastrulation and around the gastric opening of the planula
larva and the adult organism (Supplementary Fig. 1). In bilaterians,
they are continuously expressed during gastrulation and later found
around the incipient mouth and/or anus, which makes these factors
excellent candidates for the tracking of blastoporal tissue fates. We
present a comprehensive account of comparative expression data in
Fig. 5 and in Supplementary Table 2.
What do these data indicate? For Protostomia, the expression
of conserved transcription factors is in accordance with the lineage
data and emphasizes the prevalence of amphistomous gastrulation.
In annelids and mollusks (Fig. 5b–d), the blastoporal markers dis-
tribute to oral, midline and anal tissue after gastrulation, in line
with the blastopore fate mapping. In the bryozoan Membranipora,
expression of evx and cdx near the posterior blastopore and in the
later anus478 suggests that anal tissue is derived from blastoporal tis-
sue (which remains to be tested by cell tracking).
In addition, expression data has proven powerful to detect pos-
sible vestiges of amphistomy in otherwise deuterostomous species.
For example, in the deuterostomous priapulids, hemichordates and
echinoderms, the expression of blastoporal markers (foxA, brachy-
ury and gsc) has been found to label future mouth tissue, as charac-
teristic for amphistomous gastrulation (Fig. 5f,g). Can we turn this
around and find vestiges of deuterostomous gastrulation in other-
wise amphistomous patterns? For example, if deuterostomy was the
NATure Ecology & EvoluTIon Review Article
a

Nemertodermatida

Gnathostomulida
Nematomorpha

Micrognathozoa

Platyhelminthes
Euperipatoides
Xenoturbellida

Echinodermata
Hemichordata
Chaetognatha

Achaearanea

Kinorhyncha

Terebratalia
Cycliophora
Gastrotricha

Novocrania
Tardigrada
Drosophila

Platynereis
Nematoda

Entoprocta
Priapulida

Nemertea

Crepidula
Discinisca
Phoronida
Loricifera

Viviparus
Chordata

Capitella
Penaeus
Tenebrio

Bryozoa
Rotifera
Acoela

Patella
Eunice
Amphistomy

Amphistomy
Amphistomy

b
Nemertodermatida

Gnathostomulida
Nematomorpha

Micrognathozoa

Platyhelminthes
Euperipatoides
Xenoturbellida

Echinodermata
Hemichordata
Chaetognatha

Achaearanea

Kinorhyncha

Terebratalia
Cycliophora
Gastrotricha

Novocrania
Tardigrada
Drosophila

Platynereis
Nematoda

Entoprocta
Priapulida

Nemertea

Crepidula
Discinisca
Phoronida
Loricifera

Viviparus
Chordata

Capitella
Penaeus
Tenebrio

Bryozoa
Rotifera
Acoela

Patella
Eunice

Amphistomy or
deuterostomy Observed fate of blastoporal tissue
Amphistomy or Mouth/foregut + Mouth/foregut No information
Amphistomy, deuterostomy anus/hindgut (protostomy)
deuterostomy or (amphistomy)
unique gastric
opening Anus/hindgut Unique gastric
(deuterostomy) opening

Fig. 4 | Ancestral state reconstruction of the fate of blastoporal tissue. The fate of blastoporal tissue was assessed based on an extensive survey of the
literature (Supplementary Information and references therein). Chordate gastrulation is classified as amphistomous, because the vertebrate blastoporal
lip gives rise to the pharyngeal endoderm (that is foregut) — but not to the mouth proper (see text). Note that the interpretation of onychophoran
gastrulation is disputed; we consider amphistomy the most parsimonious interpretation of the currently available evidence (see discussion in
Supplementary Information). Ancestral states were inferred by the maximum parsimony method using Mesquite v.3.31 and are written on the ancestral
nodes for Eubilateria, Protostomia and Deuterostomia. If there is more than one most parsimonious possible ancestral state, all possibilities are listed.
a, Reconstructed evolution of the fate of blastoporal tissue assuming the acoel gonopore is homologous to the hindgut of other bilaterians479. Under this
hypothesis, amphistomy (blastoporal tissue giving rise to oral and anal tissue) is the most parsimonious ancestral fate of blastoporal tissue for Bilateria,
Protostomia and Deuterostomia. b, Reconstructed evolution of the fate of blastoporal tissue assuming that the acoel gonopore is not homologous to the
bilaterian hindgut and that the unique gastric opening of xenacoelomorphs is of undetermined homology to the mouth or anus of other bilaterians. Under
this hypothesis, amphistomy and deuterostomy are equally parsimonious ancestral fates of blastoporal tissue for Protostomia and Deuterostomia.

ancestral state, we would expect the mouth to not express blasto- In summary, the expression of blastoporal transcription factors
poral transcription factors despite its vicinity to the blastopore — in prospective mouth tissue in deuterostomous species (Fig. 5f,g)
which, to our knowledge, has not been observed. appears to shift the balance towards amphistomy; however, we

Nature EcoloGy & Evolution | VOL 2 | SEPTEMBER 2018 | 1358–1376 | www.nature.com/natecolevol 1363
Review Article NATure Ecology & EvoluTIon

a Acoela: Convolutriloba b Mollusca: Patella c Annelida: Platynereis d Annelida: Capitella

Anterior blastopore: 21 Anterior blastopore: future stomodeum
2b2 2b
2a2 future stomodeum Closing
1b22 Future 12 22
2b 22 Blastopore
2b
21
3a blastopore
mouth 4b
Gastrula

3b
3b
22
4B 4A 3a
21 Closing
3a 2a
22 blastopore

22
3b 3A 4c 4a
3B

2c
Ml 4C 12
12 4D 3d21 3d12 2a ?
Mr 3c 21
3c 22 22
11 3c 3d 11
1a22 3c 22 3d
212 2d
Blastopore Future 2d
gonopore Posterior Posterior blastopore: future proctodeum
blastopore:
Early larva/ organogenesis

future proctodeum Foregut

Foregut
Neural
midline
Neural
midline
Mouth
Axochord Axochord
Axochord Axochord
Hindgut
Mouth
Closed
Gonopore Future blastopore Ventral view
anus Hindgut
Lateral view

Spiralia
Protostomia

e Onychophora: Euperipatoides f Priapulida: Priapulus g Echinodermata: Asterina h Chordata: Danio rerio

Future Anterior Migration to

mouth blastopore the anterior
Gastrula

Blastopore

Mouth–
anus Yolk
furrow Future
Future mouth/ Yolk
Posterior anus foregut Future
mouth involution
pit
Future
anus/ Involution
Future Involution Involution Posterior
hindgut Blastopore
anus Blastopore blastopore Prechordal plate/
Mouth Blastopore pharyngeal endoderm
Early larva/organogenesis

Mouth

Mouth
Notochord
Future
ventral Ventral
midline extra-
embryonic
ectoderm Anus Anus
Anus Future
anus
Ecdysozoa Deuterostomia

Convergence Cell migration

Open Closed goosecoid foxA brachyury foxA+brachyury evx + cdx extension
blastopore blastopore

Fig. 5 | Gene expression in the circumblastoporal tissue. The open blastopore is indicated by a continuous red line and the closed blastopore by a dashed
red line. a, Acoela: Convolutriloba. b, Mollusca: Patella. c, Annelida: Platynereis. d, Annelida: Capitella. e, Onychophora: Euperipatoides. f, Priapulida: Priapulus.
g, Echinodermata: Asterina. h, Chordata: Danio rerio. Gene expression is shown at the gastrula stage (top row) and at the early larva–organogenesis stage,
when the final arrangement of the through-gut is established (bottom row). Green, transcription factor expressed in anterior blastoporal tissue, mouth
and foregut (goosecoid). Blue, transcription factors coexpressed in posterior blastoporal tissue, anus and hindgut (cdx and evx). Brown, transcription
factors expressed around the entire blastopore (gastrula stage), and later in mouth, foregut, anus, hindgut and midline of the neural body side (foxA and
brachyury) (the neural body side is dorsal in chordates and ventral in all other bilaterians). The species sampled cover all possible fates of the blastoporal
hole: protostomy (Patella and Platynereis), deuterostomy (Priapulus, Patiria and Danio), amphistomy (Euperipatoides) and blastopore closure (Capitella). In
contrast to this diversity of fates of the blastoporal hole, expression of mouth and anus markers appear to be very conserved, and is usually first detected
at opposite poles of the blastoporal tissue and in close vicinity to each other before morphogenetic movements start increasing the distance between
mouth and anus (red arrows represent convergent extension towards the midline of the neural body side; these arrows are continuous if the movements
have been directly observed, dotted if the movements are inferred or hypothetical). Gene expression patterns are from the following references:
Convolutriloba longifissura16; Patella vulgata508–510; Platynereis dumerilii12,511,512; Capitella teleta513–516; Euperipatoides kanangrensis; Priapulus caudatus13,17; Patiria
(formerly Asterina) pectinifera; and Danio rerio517–521 (for which the following paralogues were included: cdx1 instead of cdx, evx1 instead of evx and foxa2
instead of foxA). Adapted from ref. 479, Springer Nature Ltd (a); ref. 508, Company of Biologists (b, top); ref. 522, Springer Nature Ltd (c, bottom); ref. 523,
Elsevier; and refs 13, Springer Nature Ltd, and 14, Elsevier (f).

1364 Nature EcoloGy & Evolution | VOL 2 | SEPTEMBER 2018 | 1358–1376 | www.nature.com/natecolevol
NATure Ecology & EvoluTIon
cannot rule out the option that an independently evolved open-
ing (such as a new mouth) co-opted ancient blastoporal genes479.
Is there additional, independent evidence to be taken into account?
Focus on gastrulation movements
In many bilaterians, gastrulation involves convergence and extension
movements on both left and right sides of the blastopore, which was
initially documented for vertebrates480–483 (Fig. 5k), but which has also
been observed in annelids484 (Fig. 5c,d), molluscs60, spiders485 and
insects486 (including Drosophila487 and Tribolium488). These move-
ments either drive the formation and closure of a slit-like blastopore
directly (for example, annelids and mollusks), or can be elegantly
explained as vestiges of slit-like blastopore closure (for example, ver-
tebrates15). The general occurrence of convergence and extension
movements thus generally lends support for the evolutionary sce-
narios in Fig. 1c that involve a slit-like gastric opening (options 4–7).
As characteristic for amphistomous gastrulation, however, con-
vergence and extension movements not only elongate and close the
blastoporal slit, but also move future mouth and anal cells apart
from each other15, as illustrated for molluscs and annelids in Fig.
5b–d). We can use this paradigm to challenge a possible derivation
of deuterostomous gastrulation from the amphistomous condition:
if amphistomy were indeed ancestral, we would expect the mouth to
form close to, and move away from the blastopore during and after
gastrulation (via convergence and extension movements). If instead
deuterostomy was the ancestral state, we would expect the mouth
tissue to arise at a distance from the blastoporal tissue and to remain
there. At least for the deuterostomous priapulids and starfish, the
answer is straightforward, as their future mouth tissue forms in the
vicinity of the blastopore rim after which it moves anteriorwards
(Fig. 5f,g). These data support amphistomy as the ancestral gastru-
lation mode in Protostomia and Deuterostomia and thus support
evo-amphistomy (option 4 in Fig. 1c).
However, conflicting data should still be emphasized. First, bona
fide deuterostomy without detectable anterior migration of the
mouth is found in hemichordates (Saccoglossus489 and Ptychodera490)
and in the chordate amphioxus. These would have to be interpreted as
derived states of Hemichordata and Cephalochordata. Second, some
aspects of vertebrate gastrulation seem to be in conflict with evo-
amphistomy. Although the molecular identity (brachyury, foxA and
gsc), developmental fate (notochord, prechordal plate and pharyn-
geal endoderm as well as floorplate and hypothalamus) and conver-
gent extension movements support the contribution of blastoporal
tissue to (dorsal) midline and foregut tissue, the chordate mouth
itself clearly represents a new mouth14,491. This observation would
support evo-deuterostomy (option 6 in Fig. 1c) — which is, however,
very difficult to reconcile with the available data for Protostomia and
Ambulacraria. Two options remain: either chordates have lost the
old amphistomous mouth (still present in Ambulacraria), in line
with evo-amphistomy; or they never possessed it. The latter would
be consistent with option 7 in Fig. 1c: under this hypothesis, the ante-
rior blastopore would have closed by evo-deuterostomy in chordate
ancestors only, and a new mouth evolved later at the anterior end
of the animal. Under both hypotheses, the chordate mouth evolved
independently of blastoporal tissue (possibly from a modified gill
slit, as suggested by amphioxus data14).
In this context, it is also important to consider the fate of the
gastric opening in the enigmatic xenacoelomorphs. These are con-
sidered sister to all other bilaterians492 (as depicted in Fig. 4) or
sister to Ambulacraria493, which puts them into an important phy-
logenetic position. Xenacoelomorphs have only one gastric opening
— additionally serving as the gonopore (for example, Xenoturbella)
or with a separate gonopore (various acoels; see Supplementary
Information). This situation may represent the ancestral eumeta-
zoan state if xenacoelomorphs are sister to all other Bilateria — or
a derived condition (possibly with modification of the ancient anus
Nature EcoloGy & Evolution | VOL 2 | SEPTEMBER 2018 | 1358–1376 | www.nature.com/natecolevol
Review Article
into the acoel gonopore) if they are sister to Ambulacraria. Notably,
the acoel gonopore expresses brachyury and probably derives from
brachyury-expressing posterior blastoporal cells; in line with its
interpretation as a modified anus or cloaca479 (Fig. 5a) and with an
amphistomous interpretation of acoel gastrulation. Alternatively,
the single gastric opening in acoels may be interpreted as primary
condition — in line with option 7, which predicts the independent
evolution of the mouth and anus in Protostomia and Deuterostomia.
From nerve ring to nerve cord
In many bilaterian groups distinct ectodermal domains adjacent to
the blastopore give rise to neural tissue, often in the form of paired
longitudinal nerve cords with variable distance from the midline.
Circumoral nerve rings have also been found in some members of
the bilaterian sister group Cnidaria494, although the ancestrality of
this pattern for cnidarians remains to be tested. Together with the
brain, the paired main nerve cords are the most prominent parts of
the nervous system, as previously noted495. The ancestral presence of
ventral (or ventrolateral) nerve cords in the last common PDA has
classically been accepted by most authors, but has been questioned
in one recent study496. However, an ancestral state reconstruction
of the bilaterian nervous system supports the presence of a main
(paired or unpaired) nerve cord and of a brain in this ancestor with
high support (Supplementary Figs. 6, 7), and further indicates that
its ventral nerve cord was patterned by the staggered expression of
mediolateral-patterning neurogenic genes (Supplementary Fig. 8)
as is seen in modern vertebrates, annelids and insects, among oth-
ers497. The ventrolateral nerve cords are easily recognized in almost
all protostomians, and oral and anal loops are observed in a number
of phyla (Fig. 6a). In species with spiral cleavage, the ventrolateral
nerve cords differentiate from the 2d cells. Their anterior end takes
the shape of a loop around the foregut and becomes a smaller or
larger integrated part of the brain; it is here referred to as the ‘oral
loop’. The posterior ends often form a smaller anal loop around
the hindgut. The enteropneusts have ventral and dorsal nerves and
a collar cord498 (which is not homologous to the chordate neural
tube499) — but no ‘brain’. The collar cord is here interpreted as dorsal
(and the mouth ventral)500 and the ventral nerve cord accordingly as
homologous to that of the protostomes. This overall arrangement
of oral loop–paired ventral nerve cords–anal loop, developing from
periblastoporal neural ectoderm is found in many bilaterian groups
(Fig. 6a). This supports the notion of evo-amphistomy in the bila-
terians if one assumes that a ring-like nervous concentration was
present around the gastric opening in the bilaterian stem line.
The trochaea theory
The characteristic ciliary patterns of planktotrophic trochophora
larvae of annelids, molluscs and entoprocts provide independent
information about the fate of the blastopore in these groups. All
three phyla show a preoral protrotroch, a postoral metatroch, a peri-
anal telotroch60,501,502 (plus sometimes a gastrotroch along the ventral
midline; Fig. 6b). The feeding structure of prototroch, adoral ciliary
zone and metatroch functions as a downstream-collecting system
based on the ‘catch-up’ principle503. The telotroch is locomotory.
The trochaea theory4,504,505 proposes a series of adaptive modi-
fications of an ancestral ring of compound cilia at the blastoporal
rim of a modified gastraea, the trochaea, leading to the prototroch,
metatroch and telotroch of the trochophora larvae. The lateral blas-
topore lips fused by evo-amphistomy, so that the anterior part of the
archaeotroch became the prototroch plus metatroch, and the poste-
rior part the telotroch, whereas the intermediate part disappeared.
The adoral ciliation of the trochaea was retained as the adoral ciliary
zone plus the gastrotroch. In this scenario, the periblastoporal band
of compound cilia of the trochaea was associated with a ring nerve
that became the paired ventral nerves with an oral and an anal cili-
ary loop seen in many phyla (Fig. 6).
1365
Review Article NATure Ecology & EvoluTIon

a Bilaterian nervous systems

Annelida Tardigrada
Cerebral Oral loop Midgut (endoderm) Anal loop Cerebral ganglia
ganglia Oral loop of VNR
Mouth area
Nerves associated
with the pharynx
Outer commissure
Mouth Pharynx (stomodaeum) Ventral nerve cord(s) Anus

Mollusca
Cerebral Oral loop Midgut (endoderm) Rectum (proctodaeum) Ventral nerve
ganglia cord with ganglia

Onychophora
Mouth Pharynx Ventral Anal loop Anus
(stomodaeum) nerve cord(s) Cerebral ganglia
with eyes
Nemertea
Cerebral Oral loop Proboscis apparatus Anal loop
ganglia Oral loop

Oesophagus

Ventral nerve cord

Mouth Pharynx Midgut Ventral Anus
(stomodaeum) nerve cord
Gastrotricha Rectum
Brain Midgut (endoderm) (proctodaeum) Anal loop

Anus
Anal loop
Mouth Pharynx Ventral Anus
(stomodaeum) nerve cord Arthropoda
Nematoda Protocerebrum =
Brain Midgut (endoderm) Lumbar ganglion (anal loop) cerebral ganglia
with eyes
Deutocerebrum =
oral loop
Mouth
Mouth Pharynx Ventral Gonad Anus Tritocerebrum
(stomodaeum) nerve cord
Enteropneusta Mandibular
Anterior nerve ring Collar cord Oral loop Ventral nerve Dorsal nerve neuromere

Ventral nerve cord

with ganglia

Mouth Pharynx Gill slits Midgut Anus

(stomodaeum) (endoderm)

Apical organ
b The trochaea theory Prototroch Episphere with primary
Cerebral ganglia
Adoral ciliary zone Oral nerve loop prototroch cells
Adoral Secondary prototroch cells
Mouth 1q
ciliary Mouth Adoral ciliary zone
zone
Gastrotroch 2b 3b 3a 2b Stomodaeum
Metatroch 2c 2a
Ventral Metatroch cells
Gastrotroch nerve cords 3c 3d 2a
3c Gastrotroch cells
Telotroch Anal nerve loop 2c
Mouth Anus Approximate position
Archaeotroch Anus 2d
of future proctodaeum
Circumblastoporal nerve
Trochaea (adult) Trochophora larva Adult bilaterian Crepidula embryo

Fig. 6 | Morphology of the central nervous system in bilaterians and the evolution of a bilaterian ancestor from the trochaea. a, Examples of bilaterian
central nervous systems. Left, left lateral views; right, dorsal views with the gut omitted. Green, ventral nervous system; yellow, cerebral ganglia (when
identified). Annelida (Platynereis) images based on refs 507,524,525. Mollusca (a solenogaster) image based on ref. 526. Nemertea (a hoplonemertine) (the
origin of the proboscis apparatus is uncertain) images based on refs 527–529. Gastrotricha image based on ref. 530. Nematoda (Caenorhabditis) image based on
ref. 531. Priapulans and kinorhynchs have very similar central nervous systems532,533. Enteropneusta image based on ref. 534. Tardigrada (embryo of Hypsibius)
image based on ref. 535. Onychophora image based on ref. 536. Generalized arthropod image based on ref. 537. b, The trochaea theory for the evolution of the
bilaterian ancestor from the ancestor called trochaea. Left, the ancestral trochaea, a gastrula with a ring of compound cilia around the gastric opening.
Middle, trochophora larva (second left) and adult (third left) of the bilaterian ancestor. Right, lineage of the cells carrying prototroch and metatroch (and
the adoral ciliary zone) in the mollusc Crepidula. Panel b adapted from ref. 538, Royal Society.

1366 Nature EcoloGy & Evolution | VOL 2 | SEPTEMBER 2018 | 1358–1376 | www.nature.com/natecolevol
NATure Ecology & EvoluTIon
Conclusions and outlook
After more than a century of discussions, our account of old and
new information leaves only a few options for the fate of the ances-
tral gastric opening. On the basis of all of the evidence outlined
above, Sedgwick’s proposal of evo-amphistomy29 appears the most
likely course of mouth and anus evolution in the bilaterian stem,
supported by axes relationships, blastoporal tissue fates, by the pres-
ence of oral and anal nerve cord loops, and by the circumoral and
circumanal ciliary bands. This conclusion is consistent with a pre-
viously proposed hypothesis16 according to which a ‘separation of
mouth development from the blastopore’ occurred in the bilaterian
stem line and established developmental deuterostomy (which sug-
gests that before that event, mouth development was linked to the
blastopore, that is that gastrulation was initially amphistomous and
modified secondarily into a deuterostomous pattern). The remain-
ing question is when and how many times the switch to deuteros-
tomy happened — at the base of Bilateria, or several times within
Bilateria. Clearly, developmental deuterostomy did evolve from
amphistomy several times, in a number of scattered genera, such
as the annelid Eunice53 and the mollusk Viviparus52 — exemplify-
ing how the same might have happened earlier, at the base of larger
lineages, such as Chaetognatha and Deuterostomia.
It must be stressed, however, that the gastrulation of a few impor-
tant lineages (for example, hemichordates, chaetognaths) lacks any
known sign of derivation from an ancestral amphistomous pattern
in either gastrulation movements or cell lineage. Further studies of
the cell lineages in these taxa (in particular, determining the origin
of the foregut and mouth cells) should be able to determine whether
these exceptions are real or only apparent — and, if they are real,
how they affect our understanding of the origin and evolution of
the bilaterian through-gut and gastrulation patterns. Further stud-
ies could also remove remaining doubts about the reliability of the
classical embryological studies.
Finally, and in light of the partially conflicting data, we cannot
exclude the possibility that the PDA was schistostomous — that
is, possessed a gastric slit that had not yet closed (option 7 in Fig.
1c). The appeal of this solution is that evo-amphistomy and evo-
deuterostomy might both have occurred in bilaterian evolution;
yet in different lineages. A difficulty of option 7, however, is that
under our current understanding of bilaterian phylogeny, it would
require independent closure of the gastric opening in three bilat-
erian lineages (Protostomia, Ambulacraria and Chordata) — which
is less parsimonious than postulating a single closure at the base of
Bilateria.
Received: 7 July 2017; Accepted: 11 July 2018;
Published online: 22 August 2018
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Acknowledgements
We thank R. Schnabel (TU Braunschweig, Germany) for new information about
Caenorhabditis embryology.
Author contributions
C.N. conceived the paper and wrote the sections on morphology and embryology in
the Supplementary Information. T.B. wrote the sections gene expression and performed
ancestral state reconstructions. D.A. elaborated and illustrated options for mouth
and anus evolution. All three authors wrote the main paper and discussed the whole
manuscript.
Competing interests
The authors declare no competing interests.
Additional information
Supplementary information is available for this paper at https://doi.org/10.1038/
s41559-018-0641-0.
Reprints and permissions information is available at www.nature.com/reprints.
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