Download The Primary Brain Vesicles Revisited: Are the Three

Review
Received: June 7, 2011
Returned for revision: August 22, 2011
Accepted after revision: October 28, 2011
Published online: January 6, 2012
Brain Behav Evol 2012;79:75–83
DOI: 10.1159/000334842
The Primary Brain Vesicles Revisited: Are the
Three Primary Vesicles (Forebrain/Midbrain/
Hindbrain) Universal in Vertebrates?
Yuji Ishikawa a Naoyuki Yamamoto b Masami Yoshimoto c Hironobu Ito c
a
National Institute of Radiological Sciences, Chiba, b Laboratory of Fish Biology, Graduate School of Bioagricultural
Sciences, Nagoya University, Nagoya, and c Department of Anatomy and Neurobiology, Nippon Medical School,
Tokyo, Japan
Abstract
It is widely held that three primary brain vesicles (forebrain,
midbrain, and hindbrain vesicles) develop into five secondary brain vesicles in all vertebrates (von Baer’s scheme). We
reviewed previous studies in various vertebrates to see if this
currently accepted scheme of brain morphogenesis is a rule
applicable to vertebrates in general. Classical morphological
studies on lamprey, shark, zebrafish, frog, chick, Chinese
hamster, and human embryos provide only partial evidence
to support the existence of von Baer’s primary vesicles at early stages. Rather, they suggest that early brain morphogenesis is diverse among vertebrates. Gene expression and fate
map studies on medaka, chick, and mouse embryos show
that the fates of initial brain vesicles do not accord with von
Baer’s scheme, at least in medaka and chick brains. The currently accepted von Baer’s scheme of brain morphogenesis,
therefore, is not a universal rule throughout vertebrates. We
propose here a developmental hourglass model as an alternative general rule: Brain morphogenesis is highly conserved
at the five-brain vesicle stage but diverges more extensively
at earlier and later stages. This hypothesis does not preclude
the existence of deep similarities in molecular prepatterns at
early stages.
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Abbreviations used in this paper
CB
CBV
CR
D
EV
IB
IBV
IMC
KV
M
Me
MRB
My
NC
OV
P
PO
pos
R
r3
R(A–D)
RB
RBV
RR
S
SC
SMV
Sy
T
TB
caudal bulge
caudal brain vesicle
caudal rhombencephalon
diencephalon
optic vesicle
intermediate bulge
intermediate brain vesicle
intrametencephalic constriction
Kupffer’s vesicle
mesencephalon (midbrain)
metencephalon (cerebellum and pontine area)
mes/rhombencephalon boundary
myelencephalon (medulla oblongata)
notochord
otic vesicle
prosencephalon (forebrain)
polster
preotic sulcus
rhombencephalon (hindbrain)
rhombomere 3
A–D rhombomeres
rostral bulge
rostral brain vesicle
rostral rhombencephalon
somite
spinal cord
the so-called ‘midbrain vesicle’
synencephalon
telencephalon
tail bud
Dr. Yuji Ishikawa
National Institute of Radiological Sciences
4-9-1 Anagawa, Inage-ku
Chiba 263-8555 (Japan)
Tel. +81 43 206 3085, E-Mail ishikawa @ nirs.go.jp
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Key Words
Brain development ⴢ Brain vesicles ⴢ Morphology ⴢ
Development ⴢ Vertebrate
b
a
Fig. 1. A schematic figure of the primary
brain vesicles (a) and the secondary brain
vesicles (b) based on von Baer’s scheme.
Horizontal sections through ‘straightened
out’ neural tubes. Rostral is to the top.
Note that the midbrain (M) remains undivided. For other abbreviations, see the list.
Fig. 2. Early neural tubes of the lamprey (a) and shark (b) embryos. In a, the dorsal view
of a stage 23 embryo of L. japonica is shown. Rostral is to the top, and boundaries between
vesicles are indicated by lines. In b, the left lateral view of a stage I embryo of S. trazame
is shown. Rostral is to the left and dorsal is to the top. The boundaries between vesicles
or rhombomeres are indicated by vertical lines. For abbreviations, see the list. Redrawn
from Kuratani et al. [1998] and Kuratani and Horigome [2000].
Background
According to almost all current textbooks on developmental biology [for example, see fig. 9.9 of Gilbert, 2010],
the rostral region of vertebrate neural tubes develops into
three distinct swellings or the primary brain vesicles by
differential proliferation of neuroepithelial territories:
the forebrain, midbrain, and hindbrain (fig. 1a). The
brain vesicles are morphologically defined as rostro-caudally arranged dilatations of the primordial brain part of
the neural tube, and each vesicle may be composed of several smaller repetitive units known as neuromeres [Nieuwenhuys, 1998]. The three primary vesicles go on to subdivide into a series of five secondary brain vesicles. The
forebrain (prosencephalon) and hindbrain (rhombencephalon) are subdivided into the telencephalon/diencephalon and metencephalon/myelencephalon, respectively, whereas the midbrain (mesencephalon) remains
undivided (fig. 1b). According to Swanson [2000, 2003],
this developmental scheme is based on Malpighi’s classical description and studies by Karl von Baer [1828].
In order to uphold von Baer’s model, it is necessary to
show that there exist three initial vesicles in all verte76
b
Brain Behav Evol 2012;79:75–83
brates and that the fates of the vesicles follow the scheme.
Almost all investigators have agreed on the presence of
von Baer’s five brain vesicles at later developmental stages
[Nieuwenhuys, 1998]. However, von Baer’s primary vesicles may be an exaggerated view of early brain morphogenesis [Nieuwenhuys, 1998]. Streeter [1933, p. 474] could
not confirm the presence of the three primary vesicles in
the chick and stated: ‘The subdivision of the embryonic
brain into three primary brain vesicles is an arbitrary expedient rather than a natural phenomenon’. Furthermore, our recent studies on the teleost fish medaka (Oryzias latipes) have shown that the molecular prepatterns,
which are visible only by gene expressions at early stages,
do not correspond to the morphologically defined brain
vesicles [Kage et al., 2004]. It is important to survey the
early brain morphogenesis in various vertebrates because
von Baer’s scheme is currently considered to be a universal rule applicable to all vertebrates. The scheme is a basic
tenet of neuroscience. In this review, we survey previous
studies based on classical morphology as well as those
based on fate maps and gene expression patterns in different vertebrates.
Ishikawa /Yamamoto /Yoshimoto /Ito
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a
Vertebrate Primary Brain Vesicles
Brain Behav Evol 2012;79:75–83
a
b
c
Fig. 3. Camera lucida drawings of living zebrafish embryos at the
7-somite stage (a, neural-keel stage), 10-somite stage (b, neuralrod stage), and 18-somite stage (c, neural-tube stage). Left lateral
views are shown. Note that no constrictions are found ventrally,
although a few shallow constrictions are evident on the dorsal
surface of the mesencephalic region at the 10-somite stage (b). For
abbreviations, see the list.
Studies Using Classical Methods of Morphology
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Among agnathans, Kuratani et al. [1998] examined
early brain development in a lamprey Lampetra japonica
and reported the presence of two faint constrictions in
the initial brain (fig. 2a). The mes/rhombencephalic sulcus first became apparent at stage 21 of Tahara [Tahara,
1988], and later the par/synencephalic (intraprosencephalic) boundary became discernible. Hence, the early
brain is divided into three vesicles by these sulci. However, this situation is inconsistent with von Baer’s pros/
mes/rhombencephalon model because the brain is divided rostro-caudally into rostral prosencephalon, synencephalon plus mesencephalon, and rhombencephalon
[fig. 5A of Kuratani et al., 1998].
Now we turn to gnathostomes. In elasmobranchs, the
head development of the cat shark (Scyliorhinus torazame)
was examined by histological methods including scanning electron microscopy [Kuratani and Horigome,
2000]. According to that study, the rhombencephalic region differentiated much earlier than any other brain region, and the early neural tube exhibited a faint constriction at the pros/mesencephalic boundary and a distinct
rhombomere (r3) at stage I (19-day or 3.5-mm embryos)
(fig. 2b). The brain at this stage thus appears to be divided rostro-caudally into four portions, namely the prosencephalon, mesencephalon plus rostral rhombencephalon,
r3, and caudal rhombencephalon [see fig. 1A of Kuratani
and Horigome, 2000]. Therefore, the initial morphological subdivisions of the shark brain are also inconsistent
with von Baer’s pros/mes/rhombencephalon model. Describing the subsequent stage II of development (22-day
or 3.5-mm embryos), Kuratani and Horigome [2000, p.
895] wrote: ‘In S. torazame at this stage, rhombomeric
boundaries can be seen at the levels of r1/2, r2/3, r3/4, r4/5,
and r5/6, but the mid/hindbrain boundary is not detectable’.
In teleost fish, the hollow neural tube is derived from
an initially solid neural rod that is homologous to the
neural tube in other vertebrates [for a review of teleost
neurulation, see Lowery and Sive, 2004]. Kimmel et al.
[1995] reported in the zebrafish (Danio rerio) that no distinct enlargements were noticed in the early brain; the
neural rod developed directly into the neural tube having
five brain vesicles [see also Kimmel, 1993]. Our own observations confirmed their results. Although a few shallow constrictions were noticed on the dorsal surface of
the mesencephalic region at the 10-somite stage, no constrictions were found ventrally (fig. 3). Hence, the socalled three primary vesicles do not exist morphologically in the initial zebrafish brain.
In the frog (Xenopus laevis), Eagleson et al. [1995] reported that two slight constrictions appear separating the
prospective three brain vesicles at the late neural plate
stage (stage 17 of Nieuwkoop and Faber [1967]). They observed the three distinct brain vesicles in the early neural
tube at stage 20 of Nieuwkoop and Faber [1967]. In the
same species, Ten Donkelaar [1998] also described that
the three primary vesicles can be distinguished by stage
23 of Nieuwkoop and Faber [1967], based on anatomical
flexures and constrictions. Thus, von Baer’s model holds
true for the anuran neural tube.
There are many detailed studies on chick embryos. According to Vaage [1969], two main brain subdivisions are
discernible in living chick embryos at the 7-somite stage
(stage 9 of Hamburger and Hamilton [1951]: HH stage 9).
Vaage [1969] referred to these two divisions as archencephalon (the prospective prosencephalon) and deuteroencephalon (the prospective mesencephalon plus three
rhombomeres). At later stages (10-somite stage, HH stage
10), Vaage [1969] reported further transformation of the
neural tube into the prosencephalon, mesencephalon, and
at least three rhombomeres. At HH stage 10, Hamburger
and Hamilton [1951, p. 55] also described that ‘three primary brain vesicles are clearly visible’. In sharp contrast to
Vaage [1969] and Hamburger and Hamilton [1951], Streeter [1933] did not find any actual brain subdivisions when
he examined inner surfaces of the rostral neural tube in
the chick embryos at the 8-somite stage (HH stage 9–10),
although three brain vesicles appear to be present in an
external dorsal view. The opinion regarding the initial
brain subdivisions in chick embryos thus diverges considerably among different researchers [for a review, see Aroca
and Puelles, 2005]. The swellings of the subdivisions and
constrictions between them may be so faint at the initial
stages that they might be overlooked, or they might perhaps disappear or arise as artifacts during preparation. We
will further discuss chick brain vesicles in the section
Studies Based on Fate Maps and Gene Expression Patterns.
In Chinese hamster (Cricetulus griseus) embryos, Keyser [1972] reported that the first segment-like transverse
bulges or neuromeres are present in the open neural plate.
In the earliest neural tube at embryonic day 11, Keyser
[1972] reported the presence of two or three prosomeres,
one or two mesomeres, and several rhombomeres [Key78
Brain Behav Evol 2012;79:75–83
Studies Based on Fate Maps and Gene Expression
Patterns
As shown in the previous section, distinct swellings of
the three primary vesicles may sometimes be difficult to
identify based simply on observations of specimens prepared by classical methods. Therefore, it is important to
address the issues with more modern methods. To settle
the concerns, we surveyed previous reports based on fate
map and gene expression patterns, although the interpretation of the latter data requires care since gene expresIshikawa /Yamamoto /Yoshimoto /Ito
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Fig. 4. Reconstruction of a human embryo at stage 9 (1- to 3-somite stage, 20 days). Rostral is to the left and dorsal is to the top.
The tissue in the mid-sagittal plane, where the right and left
halves meet, is stippled. Note that the six earliest subdivisions, P,
M, R(A), R(B), R(C), and R(D), are identified on the neural fold
that is still completely open. Redrawn from O’Rahilly et al. [1989].
ser, 1972]. He noted: “On a superficial view the external
aspect of the brain in the E11 embryo suggests the presence of three vesicles, connected by constriction. In the
textbooks these vesicles are called prosencephalon, mesencephalon, and rhombencephalon. On closer scrutiny,
however, several segment-like structures are observed
within each of these ‘vesicles’, each possessing its own individual outline and configuration” [Keyser, 1972, p.30].
Also in human embryos, the first brain subdivisions
do not begin as vesicles but as enlargements of the neural
folds at stage 9 [O’Rahilly and Gardner, 1979; O’Rahilly
et al., 1989], before any portions of the neural folds have
closed (fig. 4). In the initial human neural tube, O’Rahilly
and Gardner [1979, p. 129] described that ‘external views
of the brain may show at most a swelling of the hindbrain,
which is united to that of the forebrain by the angulated
and relatively narrow midbrain’. It should be noted that
in these mammalian studies the terms prosencephalon,
mesencephalon, and rhombencephalon are not used to
indicate distinct dilatations of the vesicles (as illustrated
in fig. 1a) but only to point out regional locations of brain
subdivisions or neuromeres.
The studies surveyed above indicate that the standard
von Baer’s model holds true for the frog, but less so for the
chicken, and poorly for most other vertebrates. Those
previous reports rather suggest diversity among vertebrates in the process of early brain morphogenesis. The
swellings that indicate prospective brain subdivisions occur prior to neural tube closure in mammalian embryos
but later in many other vertebrates. The rhombencephalic region differentiates much earlier than other brain subdivisions in shark embryos. The numbers and fates of the
earliest brain vesicles are also diverse: while frogs have
three von Baerian brain swellings, zebrafish have none,
and sharks have four. Lampreys exhibit three brain swellings in early development, but they do not follow von
Baer’s scheme.
Fig. 5. Left lateral view of the medaka embryo at Iwamatsu’s stage
19 (2-somite stage). Rostral is to the left and dorsal is to the top. A
photograph of a living embryo is shown in (a), accompanied by
the corresponding line drawing (b). In b, the axial mesendoderm
and the notochord (NC), both of which are identified by the ex-
sion may change over time during development. These
types of investigations have been performed only in a few
vertebrate species. We review in this section the studies
on medaka, chick, and mouse embryos.
b
pression of shh, are shown as black and striped, respectively. Note
that the rostral brain vesicle (RBV), intermediate brain vesicle
(IBV), and caudal brain vesicle (CBV) are present. For other abbreviations, see the list. Reproduced and redrawn from Ishikawa
[1997] and Kage et al. [2004].
has shown that compartments defined by cell migration
boundaries are established as early as at stage 16+ [Hirose et al., 2004]. These results are consistent with our
interpretation of wnt1 expression (fig. 7). Therefore, von
Baer’s scheme does not hold true for medaka.
Medaka Embryo
The medaka is one of the fish models used for studies
of vertebrate developmental genetics and comparative genomics [Ishikawa, 2000; Kinoshita et al., 2009]. The general development of medaka has been described by
Iwamatsu [2004], and the brain morphogenesis has been
studied based on a fate map and gene expression patterns
[Hirose et al., 2004; Kage et al., 2004; Ishikawa et al., 2008].
In contrast to zebrafish (fig. 3), three enlargements
were recognized in the medaka neural rod (Iwamatsu’s
stage 19) before five brain vesicles were established in the
neural tube [Ishikawa, 1997; Kage et al., 2004] (fig. 5). In
the latter studies we referred to the large middle enlargement as ‘intermediate brain vesicle (IBV)’ and to the two
smaller, adjacent vesicles as ‘rostral brain vesicle (RBV)’
and ‘caudal brain vesicle (CBV)’, respectively (fig. 5b).
Two independent lines of evidence showed that the
fate of the intermediate brain vesicle in medaka is quite
different from that of the so-called mesencephalic vesicle
in von Baer’s scheme. First, the expression patterns of
wnt1, which is used as a gene marker for the caudal limit
of the mesencephalon in various vertebrates, showed that
the intermediate brain vesicle in medaka develops not
only into the mesencephalon but also into the caudal diencephalon and metencephalon [Kage et al., 2004; Ishikawa et al., 2008] (fig. 6). Second, single-cell fate mapping
Chick Embryo
As mentioned above, Hamburger and Hamilton [1951]
described that the three primary vesicles become visible
in the chick embryo at HH stage 10. However, HidalgoSánchez et al. [1999] reported that the so-called ‘mesencephalic vesicle’ at HH stage 10 contains not only the prospective mesencephalon but also a rostral part of the prospective rhombencephalon. This conclusion was based
on the spatial expression patterns of developmental genes,
Otx2, Gbx2, Pax2, Fgf8, and Wnt1, all of which are implicated in specification of the mes/rhombencephalon
boundary domain [see also Martinez and Alvarado-Mallart, 1989; Aroca and Puelles, 2005] (fig. 8).
Hidalgo-Sánchez et al. [1999] noted that the morphological constriction between the so-called ‘mesencephalic’ and ‘rhombencephalic’ vesicles at HH stage 10 is not
the true mes/rhombencephalic boundary, which is defined by the Otx2/Gbx2 expression boundary, but an intrametencephalic constriction (fig. 8a). Therefore, they
proposed a new term, namely ‘mes/met vesicle’ instead of
‘mesencephalic vesicle’, to refer to the second brain swelling at HH stage 10. Their findings are consistent with the
results of fate map analyses using the chick/quail chimeric system [Martinez and Alvarado-Mallart, 1989; Millet
et al., 1996; Hollonet and Alvarado-Mallart, 1997; for a
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a
a
b
c
review see Garcia-Lopez et al., 2009]. Thus, in both chick
and medaka embryos, the fates of initial brain vesicles are
inconsistent with von Baer’s scheme.
Mouse Embryo
Finally, we review developmental studies on the mouse
brain. As in cases of the Chinese hamster and human embryos, the first brain subdivisions (prosencephalon, mesencephalon, and two rhombomeres A and B) emerge not
as vesicles but as enlargements of the neural folds in the
mouse embryo at Theiler’s stage 12 (1- to 7-somite stage,
E8–8.5 days), when the neural folds begin to close in the
occipital/cervical region [Theiler, 1989; Kaufman, 1994].
80
Brain Behav Evol 2012;79:75–83
Fig. 7. Five neural subdivisions in medaka embryos at Iwamatsu’s
stage 16+ (neural-plate stage), 17 (neural-keel stage), 19 (neuralrod stage), and 24 (neural-tube stage). Rostral is to the left and
dorsal is to the top. Developmental changes of the telencephalic
(T), diencephalic (D), mesencephalic (M), rhombencephalic (R),
and spinal cord (SC) compartments are indicated by vertical lines.
The rostral limit of the rhombencephalic compartment is indicated by broken lines. It is situated rostral to the caudal limit of
the mesencephalon because of the rostral protrusion of the valvula cerebelli in teleost fish. Note that the boundary between M
and R is located in the caudal one third of the intermediate brain
vesicle (IBV) at stage 19 (thick vertical line). For other abbreviations, see the list. Redrawn from Hirose et al. [2004].
Numerous studies of gene expression patterns have
been reported in mouse embryos during neurulation [for
reviews see Rubenstein et al., 1998; Martinez and Puelles,
2000]. Wnt1, En1, and Pax2 are expressed in the presumptive mes/rhombencephalon boundary domain in
the neural plate as early as at the 1-somite stage (Theiler’s
stage 12), when the entire dorsal view of the neural plate
exhibits a simple spoon shape [Rowitch and McMahon,
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Fig. 6. Expression of wnt1 in medaka embryos at Iwamatsu’s stage
19 (a, 2-somite stage), 21 (b, 6-somite stage), and 22 (c, 9-somite
stage). The drawings illustrate specimens stained with wholemount in situ hybridization. Intensely and weakly expressed areas
are black and stippled, respectively. Left panels show the left lateral views (rostral is to the left and dorsal is to the top), and right
panels show the dorsal views (rostral is to the top). Note that the
boundary between the future mesencephalon and rhombencephalon (M/R) exists at the caudal one third of the intermediate brain
vesicle (IBV). For other abbreviations, see the list. Redrawn from
Kage et al. [2004] and Ishikawa et al. [2008].
b
a
b
Fig. 8. Schematic figures of chick embryos at HH stage 10 (a) and
at HH stage 20 (b). Dorsal (a, rostral is to the top) and right lateral views (b, caudal is to the bottom and dorsal is to the left) are
Fig. 9. Schematic drawings of the mouse neural plate at the 1-somite stage (a) and the 7- to 8-somite stage (b). Dorsal views of the
flattened neural plates are shown (rostral is to the top). In b, the
shown. Otx2 transcripts are expressed in dark gray areas and
Gbx2 transcripts in dotted areas. Note that the mes/rhombencephalic boundary (MRB) is present within the so-called ‘midbrain
vesicle’ (SMV) at HH stage 10. For other abbreviations, see the list.
Redrawn from Hidalgo-Sánchez et al. [1999].
expression pattern for each gene is shown on the right side of the
neural plate, and the three bulges [rostral (RB), intermediate (IB),
and caudal bulges (CB)] and the future brain subdivisions are indicated on the left side of the neural plate. Wnt1 transcripts are
expressed in dotted areas and Fgf8 transcripts in the dark gray
area. Note that the IB develops into the mesencephalon (M) and
rostral rhombencephalon (RR). For other abbreviations, see the
list. Redrawn from Rowitch and McMahon [1995] and Rubenstein
et al. [1998].
1995] (fig. 9a). Rubenstein et al. [1998] showed in their
figures that three rostro-caudally arranged transverse
bulges, each of which is marked by shallow lateral notches such as the preotic sulcus (pos in fig. 9b), were present
in the flattened neural plate at the 7- to 8-somite stage
(Theiler’s stage 12–13) [see also Lawson and Pedersen,
1992; Inoue et al., 2000] (fig. 9b). Fate map analyses
showed that the rostral, intermediate, and caudal bulges
develop into the prosencephalon, mesencephalon plus
rostral rhombomeres, and caudal rhombomeres, respectively [Rubenstein et al., 1998; Inoue et al., 2000] (fig. 9b).
Moreover, Rubenstein et al. [1998] showed that Wnt1 and
Fgf8 are expressed in transverse domains that approximate the prospective mes/rhombencephalon boundary
in the intermediate bulge [see also Crossley and Martin,
1995].
Thus, although the three bulges in the mouse neural
plate at the 7- to 8-somite stage are not brain vesicles by
definition, they seem to be equivalent to the so-called
three primary vesicles in the chick neural tube at HH
stage 10 in terms of their positions and fates (compare
fig. 9b with fig. 8a). That is, both the mouse intermediate
bulge and the so-called chick ‘mes/met vesicle’ develop
into not only the mesencephalon but also the rostral
rhombencephalon.
The neural tube begins to close in the prosencephalic
region at Theiler’s stage 13 (8- to 12-somite stage, E8.5–9
days) and is completely closed at the 15- to 18-somite
stage (Theiler’s stage 14, E9–9.5 days) [Kaufman, 1994].
According to Kaufman [1994], the three vesicles (prosencephalon, mesencephalon, and rhombencephalon) are
formed upon neural tube closure. To our knowledge,
however, the anatomical relationship between the three
bulges in the neural plate at the 7- to 8-somite stage and
the three primary vesicles identified by Kaufman [1994]
in the earliest neural tube has not yet fully been documented during mouse neurulation. If neural tube closure
is simply tardy in the mouse and the mouse intermediate
bulge at the 7- to 8-somite stage develops into the ‘mes/
met vesicle’ of Hidalgo-Sánchez et al. [1999] at the 15- to
18-somite stage, the situations of mouse and chick embryos would become much the same. Further detailed
studies will be needed to clarify this point in the mouse.
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Conclusion
Although von Baer’s three primary vesicles are present
in the frog neural tube, there exists rather large morphological divergence in the earliest neural tube in many other vertebrate taxa. Even when three vesicles are present,
their fates are different from those of von Baer’s model at
least in lamprey, medaka, and chick embryos. Thus, our
review of the literature shows that there are many ‘exceptions’ to von Baer’s rule. We have no choice but to conclude that the existence of three primary vesicles that follow von Baer’s scheme is not a universal rule throughout
vertebrates. In short, deep similarities may exist in molecular prepatterns, but little morphological similarity is
visible at early stages.
Are there any alternative rules in vertebrate brain
morphogenesis other than von Baer’s model? Because five
brain vesicles are generally noticed at later developmental
stages of vertebrate brain morphogenesis [Nieuwenhuys,
1998], the early variation in brain vesicles may fit the de-
velopmental hourglass model [Gilbert, 2010]. According
to this model, embryonic development exhibits a conserved developmental stage or period, the so-called phylotypic stage, at which morphological similarity is maximal between the members of each animal phylum [Slack
et al., 1993]. The strong similarity at this stage may be due
to the phyletic constraints [Hall, 1998]. Importantly, development is much more variable before and after this
phylotypic stage. This hourglass model may be applied
also to the morphogenesis of vertebrate brains [Kage et
al., 2004]. Before and after the middle, five-vesicle stage,
vertebrate brain morphogenesis diverges extensively.
Acknowledgements
We thank Dr. K. Maruyama and Ms. K. Maeda for their support and Dr. T. Konishi for supplying zebrafish eggs in the National Institute of Radiological Sciences.
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