Advances in Bioscience and Biotechnology, 2012, 3, 669-678 ABB Published Online October 2012 (
Apoptosis in amphibian development
Jean-Marie Exbrayat, Elara N. Moudilou, Lucie Abrouk, Claire Brun
Université de Lyon, UMRS 449, Biologie Générale, Université Catholique de Lyon, Reproduction et Développement Comparé,
Ecole Pratique des Hautes Etudes, Lyon, France
Received 13 August 2012; revised 20 September 2012; accepted 28 September 2012
Amphibians and more particularly X. laevis are mod-
els often used for studying apoptosis during embry-
onic development. Using several methods, searchers
determined the localization of programmed cell
deaths (PCD). Several experimental methods also
have been used to understand the regulatory mecha-
nisms of apoptosis, throughout development, contrib-
uting to elucidate the general action of several genes
and proteins. Apoptosis occurs very early, with a first
program under control of maternal genes expressed
before MBT, in order to eliminate damaged cells be-
fore gastrulation, and a second program at the onset
of gastrulation. PCD is also observed during neurula-
tion. Then, apoptotic cells are observed in amphibian
organogenesis and metamorphosis. Results of these
researches showed both importance of PCD for em-
bryonic development, and the complexity of its regu-
lation. Results obtained can be useful to understand
others aspects of the importance of apoptosis, par-
ticularly pathological aspects.
Keywords: PCD; Apoptosis; Development;
Metamorphosis; Amphibian; Xenopus
Amphibians reproduce in water with an external or in-
ternal development at the end of which the tadpole or
larva brings on metamorphosis, turning in a terrestrial
adult. Apoptosis being a major event on metamorphosis,
amphibians, and more especially Xenopus laevis are
useful models to study programmed cell death [1-4]. A
synthesis of works about apoptosis, obtained from am-
phibians is given here.
Eggs and early embryos of amphibians are characterized
with the presence of a pigmentation which clearly indi-
cates a bilateral symmetry. Fertilized eggs immediately
divide to give the first two blastomeres which continue to
divide becoming a morula. An inner cavity, the blasto-
coel, appears in the mass cell of the embryo, becoming a
blastula. During this period of cleavage, the size and
shape of embryos do not vary. Before mid blastula tran-
sition (MBT), zygotic genes do not express excepted
those encoding for proteins implicated in membrane
building. Maternal mRNAs previously accumulated in
the oocytes remain present in the cytoplasm of zygote
and they are distributed into the cytoplasm of blas-
tomeres during cleavage. These maternal mRNAs encode
for proteins which will be implicated in expression of
zygotic genes. In post-MBT, zygotic genes express ac-
cording to maternal signals. After cleavage, cells dis-
place during gastrulation, at the end of which ectoderm,
mesoderm and endoderm are installed. The archenteron
or primitive intestine is observed. After gastrulation, on
the dorsal part of the embryo, the neurectoderm origin-
nates successively the neural plate, then neural folds
which fuse to form the neural tube. The dorsal part of
mesoderm differentiates onto notochord and somites.
After neurulation, the end of which being characterized
by “tail-bud” stage, organogenesis occurs. After a growth
period, metamorphosis occurs. This phase corresponds to
the transfer from an aquatic to a terrestrial life and it is
characterized by the modification, development, or re-
gression of sev er al organs.
3.1. Repartition of Apoptotic Cells during
Normal Development
Repartition of apoptotic cells in early stages of develop-
ment has been little described [5-7] but consistent data
have been published in developing X. laevis [8]. At the
beginning of development, first TUNEL positive cells
appear in embryos at the onset of gastrulation. Staining
was first observed such as spots or symmetric masses in
the region surrounding the blastopore. Apoptotic cells
were also found in the remaining b lastocoel. Histological
J.-M. Exbrayat et al. / Advances in Bioscience and Biotechnology 3 (2012) 669-678
investigations showed the presence of apoptotic cells on
ectoderm and internal mesoderm. At the end of gastrula-
tion, apoptotic cells described a dorsal median strip or
two parallel strips on the dorsal part of embryo, showing
the place of future neural plate. TUNEL positive cells
were found in both neuroectoderm and underlining
mesoderm. Degenerative cells were also observed in the
Japanese newt Cynops pyrrhogaster [7]. At the onset of
gastrulation, strongly pigmented cells were observed in
ectoderm and in the blastocoel. In old gastrulae, cells
showing a similar aspect were found in ectoderm, on
contact with archenteron. At the end of gastrulation, two
groups of pigmented cells were localized into the resid-
ual blastocoel and in the anterior part of archenteron.
Dead cells in Cynops pyrrhogaster and X. laevis showed
a similar repartition. In developing zebrafish Danio rerio
dead cells also presented a corresponding repartition [9,
10], showing this phenomenon of cell death at gastrula-
tion is general in lower vertebrates.
3.2. Regulation of Apoptosis during
Segmentation and Gastrulation
To understand the regulation of apoptosis, experimenta-
tions have been performed on early development stages
in X. laevis [11-13]. After irradiation with γ rays damag-
ing DNA before the first cleavage, embryo continued to
cleave. The 12 first cycles of divisions were perfectly
comparable to that of control animals with additional
divisions. Irr adiated DNA being shor ter than normal one,
its replication was faster, explaining the presence of ad-
ditional divisions. So, the time of segmentation used to
attempt gastrulation was genetically regulated by a timer.
In embryos DNA of which being broken with restriction
endonucleases before the first division, synchronization
of cleavages was not perturbed and time to attempt gas-
trulation was not modified. So, embryonic DNA was not
implicated in control of these cell cycles.
In two cells-embryos treated with α anamitine in order
to inhibit transcription, segmentation was no effected. In
embryos treated with cyclohex imide, an inhibitor of pro-
tein synthesis, cell division was stopped one hour after
the treatment. In embryos treated with a mixture of aph-
idilcoline and hydroxyurea used to block replication of
DNA, the segmentation was also stopped. All these
treatments consequently provoked a rapid and synchro-
nous death of embryos at the onset of gastrulation with
cells showing apoptotic characteristics. In addition, a
caspase activity was shown in extracts of irradiated em-
bryos at stage 10.5, contrarily in non-irradiated cleaving
embryos or gastrulae.
Two programs of cell death from segmentation to
tadpole stage have been observed [12]. One of these pro-
grams was activated at the onset of gastrulation, conse-
quent to the degradation of cells occurring before MBT.
It was supposed that the degradation of these non stable
cells was programmed by maternal genes, according to a
biological timer independent on the type of stress, cell
progression, or protein synthesis. A second program of
cell death started at gastrulation in normal embryos. In
embryos of X. laevis treated with hydroxyurea, an insta-
bility of cyclins A1 and A2 was observed at the onset of
gastrulation [14]. At this period, zygotic transcription
was necessary to suppress apoptosis in normal embryos.
In treated animals, it was not possible to maintain such
an inhibition and consequently a lot of apoptotic cells
were observed. So, the apoptotic program was sup-
pressed in early blastulae by maternal inhibitor, and the
degradation of mRNAs encoding for apoptosis inhibitors
before MBT, was then compensated with a new zygotic
transcription between MBT and gastrulation. In other
experiments, apoptosis was blocked with injection of
mRNAs encoding for BCl-2. Results confirmed that ma-
ternal program was blocked with inhibitor of apoptosis.
In animal submitted to low doses of cycloheximide, de-
velopment was delayed before MBT but DNA synthesis,
and transcription started normally at the onset of gas-
trulation. All these results suggested the existence of a
checkpoint at MBT, regulated by maternal genes in order
to start apoptosis and also showed that zygotic transcript-
tion could block maternal program of apoptosis [15].
The lengthening of cell cycle from MBT was due to an
increase of phosphorylation of Tyr16 belonging to cdc2.
Resistance to apoptosis was associated to an increase of
p27 Xie1, a part of BCl-2 or Bax-2 implicated in pro- or
anti-apoptotic complexes, and an increase of protein
kinase Akt. At MBT, the degradation of cyclin E was
also regulated by an internal timer insensib le to the inhi-
bition of DNA, mRNAs and proteins [16], provoking
apoptosis at gastrulation [6]. An injection of cyclin A2
suspension did not affected early development and the
embryos were able to attempt tail-bud stage if cdk2 was
added. After MBT, an injection of cyclin A2/cdk2 char-
acteristic of G1/S phases provoked a cell proliferation,
more especially in the future epidermis disturbing the
equilibrium between division and differentiation.
In X. laevis, the maternal program of apoptosis was
activated just after MBT with an over-expression of S
adenosyl mathionine carboxylase [17], provoking a lack
of S-adenosyl methionine. Embryos developed in blas-
tula, but stopped at the onset of gastrulation at which
cells became apoptotic. This destruction was stopped
with an injection of BCl-2 mRNA. In embryos receiving
micro injection of 5-aza-CdR inducting hypometh ylation
of DNA, or 5-methyl dCTA, inducting contrarily a hy-
permethylation, cleavage was normal but embryos be-
came apoptotic at gastrulation [18]. Apoptosis was sup-
pressed in embryos injected with an inhibitor of caspases
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and the activation of caspase-9 was a stage-key for the
activation of mater nal pro gram [1 9]. XChk1 prov oked an
elongation of cell cycle [20]. If Chk1 was inhibited, the
development was normal until the onset of gastrulation at
which the embryo died, with cells entering in apoptosis.
In zygotes with two blastomeres injected with SAMDL
mRNAs, apoptosis was also observed at gastrulation [21,
22]. If these mRNAs were injected on a side only in em-
bryos with 4 to 8 cells, a large number of animals be-
came tadpoles; if embryos were 16 to 32 cells, all indi-
viduals became tadpoles with sometimes abnormalities.
Apoptotic cells originating from injected blastomeres
were found in blastocoel, even in developing embryos.
Other molecules have been signaled in order to partici-
pate to the check- point of apoptosis [23]. High levels of
p27BBP/eIF6 have been observed during development
when PCD increased. This anti-apoptotic factor was re-
lated to an increase of apoptosis in the parts of embryos
needing cell death for harmonious development [24].
Several experiments based upon the over-expression of
FoxO genes in X. laevis showed these genes were indis-
pensable for tissue differentiation but not for gastrulatio n,
even overexpression of several of them induced severe
damages in gastrulae [25]. Bix expressed in early Xeno-
pus gastrula, and an over-expression as well as a deple-
tion of Bix3 causes apoptosis [26].
In other vertebrates, embryos also exhibit the active-
tion of surveillance mechanisms, early in development,
to produce the selective apoptosis of damaged cells like
in amphibians. [27].
The interactions between embryonic layers were stud-
ied in order to understand regulation of balance between
cell survival and apoptosis [28]. Glucocorticoid-induc-
ible kinase 1 (SGK1) promoted ectodermal cell survival
during early Xenopus embryogenesis. A dorsal depletion
of SGK1 resulted in modified morphology. In transgenic
embryos, a knockdown of SGK1 caus ed apoptosis in the
ectoderm. SGK1 also stimulated production of BMP7.
Finally the existence of chain of reactions with an endo-
dermal and mesodermal pathway from PI3K to SGK1 to
the transcription nuclear factor producing BMP7 was
demonstrated, promoting ectodermal survival by de-
creasing Death Inducing Signaling Complex function. In
Xenopus, maternal p53 mRNAs and proteins seem to be
essential for development [29].
4.1. Description of Apoptosis in Normal
The presence of apoptotic cells was detected during
neurulation of X. laevis [8]. At stage 13, apoptotic cells
visualized were localized on the dorsal part of embryo,
generally distributed on two strips or a single median
strip, delimitating the neural plate from blastopore to the
dorsal part of body. Apoptotic cells were localized in the
neuroectoderme and the underlining mesoderm. At
stages 14 and 15, TUNEL labeled cells were grouped on
the anterior part of neural plate. At stages 16 and 17,
apoptotic cells were particularly numerous on both the
anterior and dorsal parts of embryos, corresponding to
nervous system. The most intense TUNEL staining cor-
responded to the presence of primary sensorial neurons.
Staining was particularly intense in the region of future
brain, at the place of olfactive and otic placodes. Com-
parable data have been obtained in the zebrafish Danio
rerio [9]. At the end of the stage of neural plate, the
number of apoptosis decreased comparatively to previ-
ous stages. In some embryos, apoptosis were also visual-
ized in the notochord [30], and they became more and
more numerous till the end of neurulation, with an ante-
rio-posterior pattern of distribution. If apoptosis was in-
hibited in mesodermal explants of notochord, this one
became twice longer than in control, but in some em-
bryos, notochord lacked a recognizable structure, apop-
totic cells were observed in the tail but somites were not
affected. Apoptotic cells appeared in neural crests. From
stage 26 to 28, apoptotic cells were distributed in two
symmetric areas in brain, and also observed in eyes, spi-
nal cord and tail. Cell deaths were also observed on neu-
ral tube in two neurulae of Cynops pyrrhogaster, with a
distribution like in X. laevis [6].
4.2. Regulation of Apoptosis at Neurulation
During neurulation, several primary neurons visualized
with N tubulin became apoptotic, like in sensorial pla-
codes in which apoptosis w ere observed prior the forma-
tion of synapse. In X. laevis, this part of embryo was
under the expression of the homeobox gene Xotx2 but, at
the beginning of neurulation, the expression of Xrx1 oc-
curred and expression of Xotx2 stopped. The first defini-
tion of the territories of retina on diencephalon in early
neurulae resulted from the repression of Xotx2 by Xrx1.
So, Xrx1 could be implicated on properties of the ante-
rior part of neural plate in order to develop the anterior
brain and eyes [31]. In X. laevis embryos in which cell
proliferation was blocked, the spatio-temporal pattern of
apoptosis remained unaffected in neuroectoderm if they
contained half the normal number of cells. An over-ex-
pression of Bcl-2 during primary neurogenesis of Xeno-
pus embryos stopped PCD. After inhibition, the normal
neurogenesis was disrupted with perturbation of expres-
sion domains of several genes. Yet, inhibition of PCD
did not affect the outcome of lateral inhibition. These
experimentations demonstrated that PCD regulated pri-
mary neurogenesis at the level of neuronal determination
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In Xenopus POSH (Plenty of SH3s) was implicated in
the development of anterior brain, and essential for
apoptosis when it was mediated by c-Jun N-terminal
kinase (JNK) [33]. The importance of expression of gene
XBtg2 was demonstrated in Xenopus neural development
[34]. The expression of this gene was found on the ante-
rior part of neural plate and the neural crests at mid-
neurula stage. If XBtg was inhibited on only one side of
embryo, formation of eyes became impaired, and the
anterior neural development disrupted. In embryos in
which XBtg2 was depleted, a decrease in the expression
of neural genes was observed in anterior brain, but nei-
ther in neural crests nor in epidermis, suggesting XBtg2
implicated for the differentiation of the anterior neural
plate in which its depletion provoked an increase of both
cell apoptosis and proliferation.
In X. laevis, msx1 gene acted as a factor promoting
apoptosis, and Slug gene acted as an anti apoptotic factor
[35-39]. Both the anti-apoptotic gene Bcl-2 and the
apoptosis-promoting gene Bax disturbed the expression
of these genes. A Slug over-expression provoked an
enlargement of the neural crests and derivatives. Region
of neural crests in which Slug was expressed, did not
undergo apoptosis, and region in which msx1 was ex-
pressed became apoptotic in the part of neural folds ad-
jacent to the neural crest. The balance between these two
antagonist genes controls the formation of neural crest
cells and derivatives. Prohibitin 1, an inhibitor of cell
proliferation, presented a function in development of
neural crests. Its gene Xphb1 was maternally and zygoti-
cally expressed. In neurula transcripts, it accumulated in
the neural tube and the neural crests [40]. Inhibition of
Prohibitin1 resulted in the loss of expressions for several
genes whereas other genes were not affected. E2F1-
binding domain was necessary for the action of Xphb1 in
development of neural crests [40].
The repartition of p27BBP/eIF6, a protein the decrease
of which was accompanied by a reduction in prolifera-
tion of several cells in eIF6 mice, was studied throughout
the development of Xenopus [41]. At the beginning of
embryogenesis, a correspondence between highest levels
of p27BBP/eIF6, cell proliferation and apoptosis was
observed. In later development stages high proliferation
levels were present in the same regions where higher
p27BBP/eIF6 expression was observed, while apoptosis
were not concentrated in the same sites. So, a high pres-
ence of p27BBP/eIF6 would appear in the regions where
cell death is essential for normal dev elopment [41].
Between stages 35 and 39, a high number of apoptotic
cells were observed in the whole organism, but the or-
gans essential for a free life did not present any dead
cells. Dead cells were observed especially in ventral part
of the prosencephalon and in spinal cord. The retina pre-
sented two phases of cell death [42], one at stages 37 - 38
in the ventronasal part of retina, and the other at stage 47
in retinal ganglion cell layer [43]. At stage 46, when the
hind limbs appeared [2], TUNEL positive cells were
mainly observed in the epidermis and the first generation
of gills. Few apoptosis were then observed in the second
generation of gills. During the period at which the ce-
ment gland, a transitory organ, began to degenerate,
nervous system and several organs presented numerous
dead cells [44]. At these stages, tadpoles were very sen-
sitive to environmental changes and became fragile [1,
43]. During the end of the growth period up to stage 52,
no massive cell death occurred.
6.1. Several Aspects of Apoptosis at
Amphibian metamorphosis involves dramatic remodel-
ing of organs, so a large quantity of apoptosis occurs
permitting the replacement of larval organs and tissues
with the adult ones. In X. laevis, metamorphosis is three
days long, and the end is characterized by the entire re-
gression of the tail [45-51]. Amphibian metamorphosis is
a good model to understand the mechanisms regulating
PCD [52-54]. The tail regression implicates an apoptotic
pathway inducible by T3 hormone and involving some
cell death executioners [55].
At the onset of metamorphosis, numerous apoptotic
cells were observed in the spinal cord and caudal spinal
ganglia [43,47,56], and a caspase-3 activity increased
during climax in the spinal cord [48]. At stage 58, a peak
of apoptosis was observed in spinal cord [43,56]. The
number of limb motoneurons decreased strongly after
limb innervations [57-59]. From stage 61, cell death in
the spinal cord was increasingly observed affecting mo-
toneurones and ependymal cells. PCD in the motoneu-
rons started behind the onset of PCD involving sensory
neurons [43,56]). At stage 64, some nervous cells were
still observed in the residue of the tail [60]. The elimina-
tion of several retinal ganglia cells occurred during cli-
max [61,62]. It was supposed that the process of optic
nerve remodeling accompanied the displacement of eyes
from lateral to more dorsal and rostral position as the
frog acquired binocular vision studied [62,63]. The
competition for target sites might also modulate retinal
PCD [64]. Cell deaths were also observed in some brain
regions such as mesencephalon and diencephalon. The
number of apoptotic cells in the brain increased at the
onset of metamorphosis. At stage 61 numerous apoptotic
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cells were observed in the thalamus and mesencephalon.
The primary sensory Rohon-Beard neurons [65] and the
giant Mauthner’s neurons in the hindbrain regressed
during metamorphosis, between stages 50 to 55 [66,67].
The expression of the xR11 gene prolonged the survival
of the Rohon-Beard cells and limited the morphological
changes of Mauthner’s cells [67,68] but did not affect the
disappearance of motone urons of spinal cord.
At climax, the muscles of the tail totally regressed [10,
45]. At stage 57, muscle cells began to be altered [40,51]
and fast muscular fibres were deleted first [59]. At stage
62, TUNEL positive cells of muscle were detached from
the extracellular matrix and died [60] and finally caudal
muscles were removed [53,69]. Cell death occurred also
in the dorsal muscles which do not express the adu lt con-
tractile proteins, in order to be progressively replaced
with adult muscle [70]. Caspase-3 activity and Bax
mRNA [71] increased in muscle cells during the climax,
suggesting that death of tail muscle cells implicates a
caspase-dependent pathway. Bax gene is regulated dur-
ing metamorphosis [72]. The regression of tail implicates
an apoptotic pathway inducible by T3 hormone [58].
Caspase 9 mRNA was expressed in the tail before
metamorphosis and increased before and during climax,
the production of active forms of caspase 9 increased in
muscle tissue as metamorphosis progressed [73].
At metamorphosis, the cells of larval intestine became
apoptotic, and they were replaced with non-differentiated
cells in order to form adult intestine [74-76]. TRβ par-
ticipated to apoptosis of larval intestine; close relation-
ship between the epithelium and the connective tissue
was evident during the intestinal remodeling [77-79].
The occurrence of apoptosis was also demonstrated in
the different parts of digestive tract during metamorphic
remodeling in Rana pipiens and Ceratophrys ornata lar-
vae [80]. Matrix metalloproteinase MMP-9TH was re-
sponsible of apoptosis in the larval epithelial through
degrading ECM components in the basal lamina, whereas
MMP-9 was involved in the removal of dying epithelial
cells during intestinal remodeling [81]. Digestive tract
was remodeled under the control of epithelial-connective
tissue interactions. In larval epithelial, cells underwent
apoptosis, while a small number of stem cells prolifer-
ated and differentiated to form adult epithelium [82]. In
liver, gene expression changed drastically but no major
morphological changes were observed [76].
In the skin, the outer two-cell layers of the epidermis
died by apoptosis during the climax [59], showing the
presence of caspase-3 [83]. At metamorphosis, number
of larval red blood cells decreased whereas adult ones
increased. During metamorphosis, many larval red blood
cells expressed TUNEL-positive reactions in the spleen
6.2. Regulation of Metamorphosis and Apoptosis
Thyroid hormones, T3 and T4 start amphibian meta-
morphosis [51]. T3 and T4 concentrations present a peak
at stages 58 to 66. Thyroid hormones regulated genes
expression through its nuclear receptors (TRs). In Xe-
nopus, TRβ genes were highly expressed only during
metamorphosis [85]. Xenopus TRβ genes were regulated
in a cell-type specific manner [86], and implicated in
both inducing apoptosis and stimulating cell proliferation.
TRs could form heterodimers with retinoic receptor
binding with the thyro id hormone response element situ-
ated in the target gene promoter which they active in
presence of thyroid hormone during metamorphosis, so
thyroid hormone receptors and 9-cis retinoic acid recep-
tors were required for mediating the regulation of the
genes [49,87,88]. Many genes were up-and down-regu-
lated by thyroid hormone in the regressing tail [89]. TH
also played a direct role in neurogenesis during devel-
opment of connections between the spinal cord and
The developmental expression of thyroid hormone re-
sponse genes, encoding extracellular matrix-degrading
metalloproteinases, suggested that extra cellular remod-
eling plays an important role, including cell death, cell
proliferation and differentiation. Since some years, stud-
ies concerning the role of extra-cellular matrix have been
published, showing its importance on metamorphosis [87,
90-93]. The expressions of MT1-MMP and GelA genes
were studied in intestine and tail of X. laevis during
metamorphosis [92]. Both genes were up-regulated when
both organs underwent metamorphosis. MT1-MMP only
was also expressed in the long itudinal muscle cells of the
metamorphosing intestine. MT1-MMP and GelA function
together in the extracellular matrix degradation or re-
modeling with independent roles in muscle development
in the intestine. At the onset of metamorphosis, the ex-
pression of lamin LA was down-regulated, but that of
lamin LIII was up-regulated only in the islets of pro-
genitor cells [94]. Then, the expression of LA became
up-regulated, whereas that of LIII became down-regu-
lated in the adult cells. Results suggested the involve-
ment of the lamins in the process of dedifferentiation
during amphibian metamorphosis.
Concentration of intracellular calcium is one of the
factors that can modulate apoptosis. So, an excessive
influx of extracellular calcium can activate enzymes
which participate to cell death. Consequently, an activa-
tion of ionotropic receptors like AMPA/kainate receptors
permeable to calcium may participate to the elevation of
intracellular calcium. In X. laevis, calpains, auxiliaries of
signal transduction for apoptosis [95], could be impli-
cated during events of metamorphosis when activated by
calcium [43]. In order to understand these complex
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mechanisms, in a first time, units GluR2/3 of AMPA/
Kainate receptors were in several organs of X. laevis
tadpoles in stages 50 and 54 [96], other organs remaining
negative. In central nervous system, periventricular ra-
dial cells, motoneurons and ganglia cells were also visu-
alized. Then, apoptotic cells were visualized in X. laevis
embryos from hatching to climax [56]. Several organs
always contained apoptotic cells. Transitory organs were
affected by apoptosis only at regression period. Nervous
cells degenerate, with a peak of apoptosis at stage 58,
just before tail regression. The effect of NBQX, an an-
tagonist of AMPA/kainate receptors of glutamate on PCD
was researched in tadpole of X. laevis at stage 46 [97,98].
The ubiquity of calpains 1, 2, 3, was observed in all the
organs, with a weak expression at early stages, increase-
ing in tadpoles and decreasing at metamorphosis [99]. In
NBQX treated animals, the number of apoptotic cells
increased variably in the organs, with a stronger label in
those particularly affected by metamorphosis [97,98].
Amphibians, with more particularly X. laevis and X.
tropicalis [100], but also other species [6,80,101] are
useful models for studying apoptosis during embryonic
development. For that, it was first necessary to give a
table of development. So, the normal table of X. laevis [2]
is a useful tool. In order to understand apoptosis during
normal development, searchers determined first the lo-
calization of cell deaths. Then, several experiments per-
mitted to understand the mechanisms of apoptosis th-
roughout development, contributing to elucidate the gen-
eral action of several genes and proteins in its regula-
tion. Apoptosis occurs very early, with a first program
under control of maternal genes used to eliminate dam-
aged cells before gastrulation, and a second program at
the onset of gastrulation. PCD was also observed during
neurulation. In mice, the role of apoptosis was studied in
the regulation of forebrain d evelopment [102 ]. In mice in
which genes Jnk1 and Jnk2 have been deleted, no apop-
totic cells were observed at stage of neural fold, and the
posterior part of hindbrain remained open in advanced
embryos; in mice for which caspase-3 was deficient, the
cerebral wall thickened with a convoluted area of cortex
in surviving embryos. Then, PCDs were observed in
amphibian organogenesis and metamorphosis. Results of
these researches showed both the complexity of PCD and
its importance for embryonic development. They can
also be useful to understand others aspects of the impor-
tance of apoptosis, particularly in pathologies.
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