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Sequence and Developmental Expression of AmphiTob,
an Amphioxus Homolog of Vertebrate Tob in the
PC3/BTG1/Tob Family of Tumor Suppressor Genes
1Marine Biology Research Division, Scripps Institution of Oceanography, La Jolla, California
2Institute of Oceanology, Academia Sinica, Qingdao, People’s Republic of China
3Max-Planck-Institut für Molekulare Genetik, Berlin (Dahlem), Germany
Tob is a member of the PC3/
BTG1/Tob family of vertebrate tumor suppressor
genes; its expression is known to inhibit proliferation of cells in vitro, but its possible roles during
normal development have not been investigated
previously. The present study concerns the structure and developmental expression of AmphiTob
in an invertebrate chordate, amphioxus. This is
the first investigation of any Tob gene during
embryological development. The 311 amino acid
AmphiTob protein is similar to vertebrate Tob
but lacks the C-terminal PQ-rich domain of the
latter. In early embryos of amphioxus, in situ
hybridization first reveals AmphiTob expression
in the hypoblast at the gastrula stage on the
likely dorsal side of the embryo. During subsequent development, expression is seen in several
tissues of the ectoderm, mesoderm, and endoderm. The most striking expression domains are
in the developing somitic musculature and dorsal
nerve cord. In the medial wall of each somite,
AmphiTob is expressed strongly by cells destined
to differentiate into the axial trunk muscles; this
pattern persists until late in the larval stage,
evidently because undifferentiated cells are continually becoming myogenic as the muscles grow.
Nerve cord cells conspicuously transcribe AmphiTob from the late neurula until the early larval
stage: Expression occurs in a few cells scattered
along the nerve cord and in a group of cells
located in the cerebral vesicle (in a region presumably homologous to the vertebrate diencephalic
forebrain). During development, an intense and transitory transcription of AmphiTob may be an early
event in cells exiting the cell cycle in preparation
for differentiation. Dev. Dyn. 1997;210:11–18.
r 1997 Wiley-Liss, Inc.
genes and growth-constraining genes (protooncogenes
and tumor suppressor genes, respectively). Such genes,
as their names indicate, were originally discovered in
mutated states that caused the hyperactivity of the
former and the impaired activity of the latter. Tumor
suppressor genes often have their most conspicuous
effects when they are completely lost from a genome, a fact
that has made them more difficult to study experimentally
than growth-promoting genes. Even so, several methodological approaches have now revealed nearly a score of
tumor suppressor genes in vertebrates (Weinberg, 1991).
Compared with vertebrate tumor suppressor genes,
those of invertebrates have been less studied. Although
many of the tumor suppressor genes so far discovered
in embryonic and adult Drosophila (Watson et al., 1994)
lack firmly established links with known tumor suppressor genes of vertebrates, the following clear homologies
have recently come to light: patched (Johnson et al.,
1996), merlin/NF2 (McCartney and Fehon, 1996), and
adenomatous popyposis coli (Hayashi et al., 1997). The
present paper concerns a gene in the invertebrate
chordate, amphioxus, that has a clear homolog with a
vertebrate tumor suppressor gene, Tob. In the vertebrates, Tob genes (Matsuda et al., 1996) are closely related
to PC3 genes (Kujubu et al., 1987; Lim et al., 1987; Fletcher
et al., 1991) and BTG1 genes (Roualt et al., 1992, 1993). All
three are rapidly expressed in response to a variety of
stimuli and have been implicated in the suppression of cell
proliferation (Rayburn et al., 1995; Matsuda et al., 1996;
Montagnoli et al., 1996).
Structurally, vertebrate PC3, BTG1, and Tob are
sufficiently similar to comprise a distinct gene family.
The proteins encoded by rat PC3 and human BTG1 are
relatively small (158 and 171 amino acids, respectively), whereas the protein encoded by human Tob (345
amino acids) is about twice the size of the other two
genes, resembling them most closely in its N-terminal
Key words: cephalochordata; myogenesis; neurogenesis
During the life history of an animal, both normal
development and adult homeostasis are ensured by a
balance between the activities of growth-promoting
Grant sponsor: NSF; Grant number: IBN 96-309938; Grant sponsor:
Natural Science Foundation of China; Grant sponsor: K.C. Wong
Education Foundation (Hong Kong).
*Correspondence to: Nicholas D. Holland, Marine Biology Research
Division, Scripps Institution of Oceanography, La Jolla, CA 920930202. E-mail:
Received April 1997; Accepted 19 May 1997
half. The proteins encoded by all of these genes have an
abundance of nonpolar amino acids at the N-terminal
end. It was originally thought that this hydrophobic
domain was involved in secretion of the gene product
(Bradbury et al., 1991), but subsequent work has shown
that the proteins function intracellularly (Roualt et al.,
1992; Iacopetti et al., 1994; Varnum et al., 1994;
Matsuda et al., 1996).
Genes of the PC3/BTG1/Tob family have been reported so far only from higher vertebrates, and the
occurrence of homologous genes in lower vertebrates
and invertebrates is an open question. The present
paper reports the discovery of a Tob homolog from the
cephalochordate, amphioxus. In addition, because the
developmental transcription patterns have not yet been
described for any Tob gene—even for the vertebrates—we describe the expression of AmphiTob during the embryonic and larval stages of amphioxus.
Obtaining DNA and Library Screening
Ripe adults of the Florida amphioxus, Branchiostoma
floridae, were collected in Tampa Bay, Florida. The eggs
were fertilized, and the embryos and larvae were
cultured at 23°C (Holland and Holland, 1993). A cDNA
library was constructed from 26-hr larval mRNA in the
pSPORT 1 vector (GIBCO-BRL, Gaithersburg, MD),
and genomic DNA for Southern blots was extracted
from a sample of 20 adults (L.Z. Holland et al., 1996).
When probing the cDNA library (60,000 clones) at
moderately low stringency (N.D. Holland et al., 1996)
with a 148-bp stretch of the paired box of the amphioxus Pax-6 gene, we incidentally obtained three strongly
hybridizing clones (29F16, 6A22, and 60K21) that we
called AmphiTob due to their homology with the human
Tob gene (Matsuda et al., 1996). The two longest clones,
29F16 and 6A22, were sequenced in their entirety. When
aligning sequences, Clustal V was used to introduce gaps.
Amino acid substitutions with Dayhoff scores of 9 or higher
were considered to be conserved (Doolittle, 1987).
Southern Blot Analysis
Southern blots of genomic DNA were prepared according to L.Z. Holland et al. (1996). To determine the
number of amphioxus genes related to AmphiTob and
the gene copy number, blots were hybridized with an
ApaI-EcoRI fragment (1,232 bp; delimited by arrows in
Fig. 1), which comprises the C-terminal two-thirds of
the coding region plus the upstream half of the 38
untranslated region. Low-stringency hybridization was
in 6 3 standard saline citrate (SSC), 0.2% sodium dodecyl
sulfate (SDS), 10 3 Denhardt’s, 1 mM EDTA overnight at
60°C. Washes were at 55°C in 2 3 SSC, 0.1% SDS.
In Situ Hybridization
The developmental expression of AmphiTob was studied
by in situ hybridizations of developing amphioxus fixed at
frequent intervals. A schedule of normal development at
23°C has been published previously (N.D. Holland et al.,
1996). The ApaI-EcoRI fragment mentioned in the preceding paragraph was subcloned into pBluescript SK1 (Stratagene, La Jolla, CA) and was used as a template for an
antisense riboprobe approximately 1,000 bp long. This
riboprobe was designed to hybridize with AmphiTob mRNA
but not with that of related genes (i.e., possible amphioxus homologs of PC3 or BTG1). Methods of fixation,
riboprobe synthesis, and in situ hybridization were
according to L.Z. Holland et al. (1996).
Sequence Analysis
Figure 1 shows cDNA of AmphiTob clone 29F16 from
B. floridae (superscripts indicate differences in clone
6A22 relative to clone 29F16). Both clones are about 2.4
kb long and code for a 311 amino acid protein with the
same amino acid sequence; thus, despite some nucleotide differences, the two clones evidently represent
polymorphic forms of the same gene. The 38 untranslated region includes three AT-rich sequences with
ATTTA motifs (starting at nucleotides 1,356, 1,745, and
2,390) that characterize genes transcribing rapidly
degradable mRNA (Shaw and Kamen, 1986). Because
there is no polyadenylation signal (AATAAA) near the
38 end of the nucleotide sequence, the 38 untranslated
region is presumably incomplete.
Figure 2A shows that AmphiTob and human Tob
(Matsuda et al., 1996) share 51% identical amino acids
(75% identities plus conservative amino acid substitutions). A comparison of hydrophobicity plots of each
protein (data not shown) reveals that the 16 N-terminal
amino acids of both comprise a very similar nonpolar
domain. Like vertebrate Tob, AmphiTob is rich in PEST
residues (stretches rich in proline, glutamic acid, serine, and threonine), which characterize relatively unstable proteins (Rogers et al., 1986). The C-terminal
half of Tob includes a PQ-rich domain that is not
present in the AmphiTob protein.
Figure 2B compares the entire amino acid sequences
of AmphiTob, rat PC3 (Bradbury et al., 1991), and
human BTG1 (Roualt et al., 1992). For AmphiTob vs.
PC3, the amino acid identities are 42%, and the identities plus conservative amino acid substitutions are
66%. For AmphiTob vs. BTG1, the amino acid identities
are 37%, and the identities plus conservative amino
acid substitutions are 65%.
Southern Blot Analysis
The Southern blot was probed with a stretch of
AmphiTob selected to avoid extensive sequence similarities to vertebrate PC3 and BTG1 genes. At low stringency, a single hybridization band resulted from digestion by 7 of 15 restriction enzymes (Fig. 3). This result
strongly suggests that AmphiTob is the only Tob gene in
the amphioxus genome and is present in a single copy.
Developmental Expression of AmphiTob
Wholemount in situ hybridization during the cleavage and blastula stages of amphioxus reveals no detect-
Fig. 1. AmphiTob clone 29F16 from cDNA of 26-hr larvae of the
Florida amphioxus, Branchiostoma floridae: nucleotide and deduced
amino acid sequences (GenBank accession number U95824). The
in-frame stop codon preceding the presumed translational start site is
underlined. The two superscript arrows delimit the ApaI-EcoRI fragment
used for the Southern blot analysis and for antisense riboprobe synthesis.
The superscript numbers locate the following differences in clone 6A22
relative to clone 29F16 (no amino acid substitutions resulted from
nucleotide differences in the coding region): 1, 58 start of clone; 2, C; 3, A;
4, T; 5, A; 6, G; 7, C; 8, C; 9, G; 10, A; 11, C; 12, A; 13, C; 14, C; 15, G; 16,
T; 17, delete ACA; 18, insert A; 19, A; 20, insert T; 21, T; 22, delete TG; 23,
38 end extended by eight additional As.
Fig. 2. A: Amino acids encoded by AmphiTob compared with amino
acids encoded by human Tob (Matsuda et al., 1996). B: Amino acids
encoded by AmphiTob compared with those encoded by rat PC3
(Bradbury et al., 1991) and human BTG1 (Roualt et al., 1992). Identical
amino acids and conserved amino acid substitutions are indicated by lines
and dots, respectively.
able expression of AmphiTob. Expression is first seen at
the late gastrula (Fig. 4A), chiefly in the hypoblast on
the probable dorsal side of the embryo (as indicated by
subsequent expression patterns). In the early neurula
stage, AmphiTob is expressed in cells that comprise the
anterior wall of the foregut endoderm and in the
Fig. 3. Genomic southern blot analysis of DNA pooled from 20
amphioxus adults. Numbers at the top of lanes refer to digestion in the
following restriction enzymes: 1, BstE II; 2, BstX I; 3, Eco0109 I; 4, EcoR V;
5, Hind III; 6, Pst I; 7, EcoR I. The blot was probed at low stringency with a
1,232-bp stretch of AmphiTob. Size markers are at left.
paraxial mesoderm (Fig. 4B), in which the presomitic
grooves are forming (Fig. 4C). By the stage of the
hatching neurula (Fig. 4D,E), expression is detectable
in the foregut endoderm, somitic mesoderm, and posterior mesoderm. In the late neurula (Fig. 4F–H), mesodermal expression is strongest in the somites (in the
medial wall, where the myoblasts are beginning to
differentiate) but is becoming less conspicuous in the
posterior mesoderm and the foregut endoderm; in addition, expression is now conspicuous in a group of cells
located in the dorsal and ventral wall of the cerebral
vesicle near the anterior end of the nerve cord and in
individual cells scattered more posteriorly in the nerve
cord. In the 24-hr embryo (Fig. 4I,J), the transcription
patterns are much the same as at the preceding stage,
although an additional expression domain is now detectable in the anterior ectoderm.
In the 30-hr larva (one-gill slit stage), expression is
present but is weaker in the somites and is no longer
detectable in the posterior mesoderm. Expression remains strong in the anterior ectoderm and in cells of the
cerebral vesicle of the dorsal nerve cord. In addition,
transcripts are now present in scattered cells in the
ventral wall of the midgut and hindgut (Fig. 4K). In the
subsequent larval stages, AmphiTob transcription diminishes in most tissues to levels undetectable by in
situ hybridization. The exception is transcription by
some cells of the somitic musculature (Fig. 4L), at least
through the 14-day larva (six-gill slit stage). The expressing cells are presumably exiting the cell cycle and
are about to differentiate into muscle cells of the axial
trunk musculature.
Vertebrates and cephalochordates have been evolving independently for half a billion years. Thus, sequence comparisons of Tob genes (and their protein
products) between amphioxus and vertebrates can indicate which regions have diverged and which have
tended to be conserved during evolution. The C-terminal
half of the vertebrate Tob protein includes a PQ-
rich sequence that is 26 amino acids long in human Tob
(Matsuda et al., 1996) and 43 amino acids long in
murine Tob (Yoshida et al., 1996). On the basis of the
PQ-rich domain, Matsuda et al. (1996) tentatively
proposed that Tob might act as a transcription factor. If
Tob proteins do include such a function, then it is a
feature peculiar to vertebrates, because AmphiTob lacks
any equivalent of the PQ-rich domain (either through
loss of an ancestral PQ-rich region in the cephalochordate line or through de novo acquisition in the vertebrate line).
For Tob proteins in general, sequence data by themselves give no clear insights into potential functions.
Although the hydrophobic N-terminal domain is not a
signal peptide involved in secretion of Tob proteins
(Roualt et al., 1992; Iacopetti et al., 1994; Varnum et al.,
1994; Matsuda et al., 1996), its function is uncertain;
for BTG1 proteins, which have a similar domain,
Roualt et al. (1992) suggested that the nonpolar domain
might anchor the protein to a cell membrane.
AmphiTob, like human and murine Tob, includes
several PEST residues, which are characteristic of
proteins with relatively short half-lives (Rogers et al.,
1986). The intracellular half-life has not been measured
directly for any Tob protein, but the half-life of PC3
protein, which has comparable PEST residues, is less
than 15 min (Varnum et al., 1994). Like the Tob protein,
the mRNA coding for it is probably also short-lived due
to the presence of ATTTA motifs (Shaw and Kamen,
1986) in the 38 untranslated regions of vertebrate Tob
(Yoshida et al., 1996) and AmphiTob.
Although transfection of Tob expression plasmids
into cultured cells represses their growth (Matsuda et
al., 1996), little is yet known about the detailed relations of Tob to other components of the growthregulating machinery. Matsuda et al. (1996) demonstrated that Tob can interact directly with at least one
member of the epidermal growth factor receptor family
(p185, which is encoded by Her2 5 erbB2/neu), resulting in the negative regulation of the antiproliferative
pathway mediated by Tob; this interaction involves
binding of Tob to the cytoplasmic domain of p185, which
is a transmembrane receptor tyrosine kinase, although
it is not yet known whether Tob is phosphorylated in
the process.
The downstream targets of Tob proteins are unknown
at present. However, it has recently been found that
PC3 and BTG1 can bind to a protein-arginine
N-methyltransferase, which, in turn, may modulate
splicing during the maturation of mRNA, with ultimate
effects on the cell cycle (Lin et al., 1996). Thus, one can
speculate that Tob might have a comparable target and
mode of action. Alternatively, it has been suggested that
PC3 might influence the phosphorylation state of the
key growth-suppressor protein, pRB, as part of an
antiproliferation pathway (Montagnoli et al., 1996).
Expression of vertebrate genes of the PC3/BTG1/Tob
family has been studied in cells stimulated by administration of exogenous inducers (Kujubu et al., 1987; Lim
et al., 1987, 1995; Bradbury et al., 1991; Fletcher et al.,
Fig. 4. Wholemount in situ hybridization showing expression of
AmphiTob in developing amphioxus; anterior in all specimens (except A)
is toward the left; all scale lines are 50 mm. A: Late gastrula in an optical
section midway along animal-vegetal axis; the hypoblast (probably on the
dorsal side) is expressing AmphiTob. B: Side view of an early neurula
embryo with expression in the foregut wall (arrow) and in the paraxial
mesoderm. C: The preceding embryo in dorsal view focused at the level of
the paraxial mesoderm; expressing cells are associated with the presomitic grooves (arrowheads). D: Side view of a hatching neurula with
expression in the foregut wall (single arrow), paraxial mesoderm, and
posterior mesoderm (double arrow). E: Dorsal view of the preceding stage
showing expression in the paraxial mesoderm and posterior mesoderm.
F: Side view of a late neurula with conspicuous expression near the
anterior end of the dorsal nerve cord (arrow) and segmental expression in
the somitic mesoderm. G: Late neurula in dorsal view focused at the level
of the notochord (n) and somitic myocoels (arrows); AmphiTob is strongly
expressed in cells in the myogenic medial wall of each somite. H: The
preceding specimen in dorsal view focused at the level of the dorsal nerve
cord; expressing cells are clustered near the anterior end (single arrow)
and are also scattered more posteriorly along the nerve cord (double
arrow). I: Side view of 24-hr embryo with expression in the anterior
ectoderm (arrowhead), nerve cord (arrow), and somites. J: Anterior
region of the preceding specimen with expression in the anterior ectoderm
and cerebral vesicle of the nerve cord. K: Side view of a 30-hr larva with
expression not only in the anterior ectoderm and nerve cord but also in the
endoderm, especially in a few midgut and hindgut cells (arrowheads).
L: Side view of a 2-week larvae showing three segments of the trunk
musculature delimited by connective tissue septa (arrowheads); within
each segment, some cells (arrow) express AmphiTob.
1991; Roualt et al., 1992; Cmarik et al., 1994), in
unstimulated cell cultures (Matsuda et al., 1996), and
also in the normal tissues of embryos (Iacopetti et al.,
1994), juveniles (Tippets et al., 1988; Lim et al., 1994),
and adults (Tippets et al., 1988; Roualt et al., 1992; Lim
et al., 1994; Rayburn et al., 1995; Matsuda et al., 1996).
In most normal tissues of postnatal vertebrates, transcription of these genes can usually be demonstrated by
Northern blot analysis; presumably, much of this expression is at a low level for maintaining tissue homeostasis, with a possible admixture of more intense expression in predifferentiation compartments of renewing
cell populations (Rayburn et al., 1995). The present
study with wholemount in situ hybridization may lack
the sensitivity to register low background levels of
transcription. Therefore, our positive reactions identify
cells that transcribe AmphiTob conspicuously. By analogy with what is known for PC3 (Iacopetti et al., 1994),
it seems likely that this intense expression characterizes cells that are exiting from the cell cycle; however,
this function of Tob during normal development has not
yet been unequivocally established.
There has been little work on expression patterns of
vertebrate PC3/BTG1/Tob genes during normal development. The one existing study, which concerned PC3 and
was focused exclusively on the developing central nervous system (Iacopetti et al., 1994), revealed that PC3
transcription transiently becomes intense in neuronal
precursor cells entering growth arrest in preparation
for subsequent differentiation. For interpreting the
present in situ data for AmphiTob expression in developing amphioxus, it also seems likely that transiently
intensified transcription of the gene occurs at the time
when cells exit the growth cycle, soon before differentiation begins. In general, it seems likely that, like Tob,
many genes that are viewed as tumor suppressors in
one context will ultimately be found to play important
roles during normal embryology.
At the gastrula stage of amphioxus, conspicuous
AmphiTob transcription in cells of the dorsal hypoblast
is one of the earliest manifestations of dorsoventral
polarity in the embryo. During the subsequent neurula
stage, many of these cells evidently differentiate into
axial trunk muscles along in the median wall of each
somite (Holland, 1996). Later in development—even in
advanced larval stages—some cells of the trunk musculature continue to express AmphiTob conspicuously,
presumably because they are on the verge of differentiating into definitive myocytes to accommodate the
continuing growth of the axial muscles.
Other obvious domains of AmphiTob expression during amphioxus development include a region in the
anterior part of the dorsal nerve cord that is probably
homologous to the vertebrate diencephalic forebrain
(N.D. Holland et al., 1996). Presumably, the intense
transcription of AmphiTob is in neuroblasts exiting the
cell cycle in preparation for differentiation. The strong
expression of AmphiTob in the wall of the developing
midgut and hindgut probably identifies cells that are
ceasing to divide prior to differentiation into unicellular
endocrine cells synthesizing peptide hormones, such as
insulin, secretin, and neurotensin (Thorndyke and Falkmer, 1985). For the vertebrates, it will be interesting to
determine whether Tob is expressed during normal
development, especially during myogenesis, neurogenesis, and the differentiation of certain endocrine organs.
We are grateful to John Lawrence and Ray Wilson for
laboratory facilities at the University of South Florida
(Tampa and St. Petersburg). The Pax-6 probe was
generously provided by Sacha Glardon. This work was
supported in part by NSF research grant IBN 96309938 to N.D.H. and L.Z.H. and also by grants to
S.C.Z. from the Natural Science Foundation of China
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