1 Graduate School of Biological Sciences, Nara Institute of Science and
Technology, 8916-5, Takayama, Ikoma, Nara 630-0101, Japan
2 Department of Molecular Embryology, Graduate School of Medicine, Chiba
University, Chuo-ku, Chiba 260-8670, Japan
3 RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehiro, Tsurumi-ku,
Yokohama 230-0045, Japan
4 Department of Developmental Neurobiology, Tohoku University Graduate School of
Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
* Author for correspondence (e-mail: takahasi{at}bs.aist-nara.ac.jp)
Accepted 11 January 2003
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SUMMARY |
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Key words: Lens placode development, Mab21l1, Mouse, PAX6, optic vesicle
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INTRODUCTION |
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Previous studies have shown that mab-21 is highly conserved in
various animal species, from vertebrates to invertebrates
(Mariani et al., 1999;
Wong and Chow, 2002b
). The
human ortholog of mab-21 has been isolated from a retinal cDNA
library (Margolis et al.,
1996
) and the first murine ortholog of mab-21 was cloned
from an embryonic mouse brain cDNA library after a search for novel genes
(Mariani et al., 1998
). We
have independently immunopurified the mouse mab-21 gene
Mab21l1 as a target candidate for HOXC4 by a method described
previously (Tomotsune et al.,
1993
). Briefly, a DNA fragment, located
2 kb upstream of the
putative Mab21l1 transcription start site, was cloned through a
search for DNA sequences binding to the HOXC4 protein in native chromatin (D.
Tomotsune and N.T., unpublished).
Two mab-21 orthologs, designated Mab21l1 and
Mab21l2, are known to exist in Drosophila, zebrafish,
Xenopus, chicken, mouse and human, whereas only one is present in two
closely related nematode species, C. elegans and C. briggsae
(Ho et al., 2001;
Lau et al., 2001
;
Mariani et al., 1999
;
Mariani et al., 1998
;
Wong et al., 1999
;
Wong and Chow, 2002b
). All
vertebrate MAB21 family proteins so far sequenced have over 90% amino acid
sequence similarity (Ho et al.,
2001
). The distribution of Mab21l1 and Mab21l2
in vertebrates partly overlap one another in the developing eye, midbrain,
branchial arches and limb buds, although mouse Mab21l1 is uniquely
expressed in the lens and genital tubercle, whereas Mab21l2 is found
in the body wall and umbilical cord
(Mariani et al., 1999
;
Mariani et al., 1998
;
Wong et al., 1999
;
Wong and Chow, 2002b
).
Functions of vertebrate Mab21l1 and Mab21l2 have been
addressed in zebrafish, Xenopus and mouse. A study using zebrafish
acerebellar (ace) and no isthmus (noi)
mutants has shown impairment of Mab21l2 expression and apparent
involvement in development of the midbrain-hindbrain boundary region
(Kudoh and Dawid, 2001).
Recently, RNA interference and antisense oligodeoxynucleotide (ODN) approaches
have demonstrated that Mab21l2 is essential for embryogenesis in
vertebrates (Lau et al., 2001
;
Wong and Chow, 2002a
). In
Xenopus, depletion of Xmab21l2 results in failure of
gastrulation and neurulation, as well as notochordal and eye defects
(Lau et al., 2001
). In the
mouse, depletion of Mab21l1 and Mab21l2 prevents neural tube
closure, notochord formation and embryonic turning, as well as eye and somite
defects (Wong and Chow,
2002a
). These observations suggest an essential requirement of
MAB21 family proteins in vertebrates as well as in C. elegans.
Although some functions of MAB21 family proteins have already been investigated using the above strategies, a genetic approach is needed to achieve a deeper and more precise understanding of these proteins. For this purpose, we generated Mab21l1-deficient mice, and revealed essential roles in lens formation and in preputial gland morphogenesis.
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MATERIALS AND METHODS |
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The PCR conditions were as follows: 35 cycles at 94°C for 1 minute, 55°C for 1 minute and 72°C for 1 minute. The predicted sizes of the PCR fragments were 145 and 255 bp for the wild-type and targeted alleles, respectively. The phenotypes of Mab21l1-/- were identical with both 129 and B6x129 hybrid backgrounds. The results described herein were obtained by analyzing mutant mice with a B6x129 hybrid genetic background.
In situ hybridization
Whole-mount in situ hybridization was performed as described
(Nieto et al., 1996) at
65°C in 50% formamide containing 5x SSC. Paraffin and frozen
sections were hybridized in situ at 65°C in 50% formamide containing 10%
dextran sulfate. The Mab21l1 and Mab21l2 probes were derived
from cDNA fragments, including the full-length coding region. Foxe3, Rx
(Rax Mouse Genome Informatics), Bmp4, Bmp7, Sox2, Maf, Chx10,
Otx2, Six3, Hes1, Brn3b (Pou4f2 Mouse Genome Informatics),
A-crystallin (Cryaa Mouse Genome Informatics),
A-crystallin (Cryga Mouse Genome Informatics),
Pax6 and Lhx2 probes have been described previously
(Blixt et al., 2000
;
Furukawa et al., 1997
;
Furuta et al., 1997
;
Kamachi et al., 1998
;
Kawauchi et al., 1999
;
Liu et al., 1994
;
Matsuo et al., 1995
;
Oliver et al., 1995
;
Sasai et al., 1992
;
Turner et al., 1994
;
van Leen et al., 1987
;
Walther and Gruss, 1991
;
Wistow and Piatigorsky, 1988
;
Xu et al., 1993
). Some probes
were derived from mouse embryo RNA by RT-PCR amplification using primers based
on published cDNA sequences. All were labeled with digoxigenin using standard
procedures.
Histology
Embryos were dissected in phosphate-buffered saline (PBS) and fixed in 4%
paraformaldehyde in PBS overnight at 4°C. The fixed embryos were
dehydrated through graded alcohols and embedded in paraffin wax, sectioned at
8 µm, and stained with Hematoxylin and Eosin.
Immunohistochemistry
Paraffin wax-embedded and frozen sections were microwave-irradiated for 5
minutes in 10 mM citrate buffer (pH 6.0), incubated in 3%
H2O2 for 10 minutes and then incubated with primary
antibodies overnight at 4°C. The anti-PAX6 antibody was diluted to 1:1000
(Inoue et al., 2000).
Antigen-antibody complexes were detected by incubation with HRP-conjugated
goat anti-rabbit IgG (Medical and Biological Laboratories, Japan) diluted
1:100 for 1 hour at 37°C, followed by visualization with diaminobenzidine
hydrochloride (DAB).
Frozen sections were prepared as follows. Embryos fixed in 4% paraformaldehyde in PBS overnight at 4°C were rinsed in PBS for 10 minutes then cryoprotected in a sequential series of 10, 20 and 30% sucrose in PBS. The embryos were oriented in OCT compound (Tissue-Tek), and rapidly frozen in liquid nitrogen. Sections cut at 14 µm were mounted on MAS-coated glass slides (Matsunami Glass, Japan).
Detection of proliferating or apoptotic cells
Pregnant mice were intraperitoneally injected with 3 mg of
bromodeoxyuridine (BrdU). Embryos were sacrificed 1.5 hours later and fixed in
4% paraformaldehyde in PBS overnight at 4°C. Sections (6 µm) of embryos
embedded in paraffin wax were microwaved for antigen retrieval as described
above, then stained with an anti-BrdU antibody using a BrdU Labeling and
Detection Kit II (alkaline phosphatase, Roche). Quantitation was performed
using five sections from three embryos of each genotype. TdT-mediated dUTP
nick end labeling (TUNEL) analysis was also performed using a In Situ Cell
Death Detection Kit (HRP, Roche).
Chimera analysis
As most Mab21l1-/- mice proved to be sterile
with natural mating, we obtained Mab21l1-/-
embryos by in vitro fertilization based on the methods of Toyoda et al.
(Toyoda et al., 1972a;
Toyoda et al., 1972b
).
Briefly, female homozygotes were superovulated by intraperitoneal injections
with 5 IU of pregnant mare serum gonadotropin (PMSG) and 5 IU of human
chorionic gonadotropin (hCG) 48 hours later. Unfertilized eggs were collected
from the ampullae of oviducts 16-17 hours after hCG injection and placed in
TYH medium equilibrated under 5% CO2. Sperm were collected from the
caudal epididymis of males and suspended in TYH medium
(Toyoda et al., 1972a
). After
capacitation for 1-2 hours,
5-10 µl aliquots of sperm suspension were
added to 0.3 ml TYH medium containing eggs, so that the final density of
spermatozoa was 150-300/µl. The efficiency of in vitro fertilization was
evaluated 6 hours after insemination by examining release of the second polar
body and the formation of female and male pronuclei. Fertilized eggs were
either incubated for another 24 hours under the same conditions or transferred
to m-WM medium for further development
(Witten, 1971
). ROSA26 Tg/+
and wild-type embryos were also generated by in vitro fertilization.
Eight-cell embryos were aggregated as described to generate chimeras
(Koizumi et al., 2001).
Chimeric embryos were harvested at a stage equivalent to 12.5 dpc, fixed in 1%
formaldehyde, 0.2% glutaraldehyde and 0.02% NP-40 in PBS for 30 minutes at
4°C, then washed twice with PBS for 30 minutes at room temperature. Fixed
embryos were stained for 2 days at 37°C in PBS containing 1 mg/ml X-Gal, 5
mM K3Fe(CN)6, 5 mM K4Fe(CN)6, 2 mM
MgCl2 and 0.02% NP-40 to detect ß-galactosidase. The embryos
were fixed again in 4% paraformaldehyde, embedded in paraffin wax and
sectioned.
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RESULTS |
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Eye and preputial gland defects in adult Mab21l1 deficient
mice
Visual inspection revealed obvious eye defects in all adult
Mab21l1 homozygotes (Fig.
2A,B). Mab21l1-/- eyes were much
smaller than in wild-type mice (Fig.
2C) and histological analysis indicated the presence of only a
rudimentary lens and revealed the lack of the iris and ciliary body in adult
homozygotes (Fig. 2D,E). The
anterior eye chamber was not formed and the prospective chamber was occupied
by pigmented cells (Fig. 2D,
part a; E, part b). The cornea was also affected so that epithelial and
mesenchymal cells were not clearly segregated
(Fig. 2E, part b). Although the
optic nerve and retinal pigmented epithelium were present, along with retinal
lamination and the major class of retinal cells, the layer was much thinner
than in the normal retina (Fig.
2E, part d).
|
Mab21l1 is required for normal lens development
Eye defects in Mab21l1-/- were obvious at
E12.5, as represented by malformed pigmented epithelium on visual inspection
under a stereomicroscope, whereas no significant difference was visible at
E10.5 (Fig. 3A,B). A lack of
any lens was manifest at E16 (Fig.
3A,B). In addition, histological analyses of E17
Mab21l1-/- fetuses revealed that the lens was
absent and that the prospective cornea and retina were significantly thickened
compared with Mab21l1+/- fetuses
(Fig. 3C,D). At E13, the lens
was absent and malformation of the retina was observed, whereas the
presumptive cornea and the pseudostratification of retina were still
morphologically normal (Fig.
3E,F). At E10.5, the lens placode failed to form a lens vesicle in
the Mab21l1-/- eye, whereas the lens pit had
already separated from the surface ectoderm and the lens vesicle was formed in
the Mab21l1+/- eye
(Fig. 3G,H). The earliest
morphological changes in Mab21l1-/- were seen at
E9.5, when the lens placode in the area in contact with the optic vesicle was
thickened to a lesser extent and narrower than in the
Mab21l1+/- embryo
(Fig. 3I,J). At E9.0, we could
not observe significant differences in the prospective eye area between
Mab21l1+/- and
Mab21l1-/- embryos. These results indicate that
Mab21l1 has an important role in the lens formation.
|
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In Mab21l1+/+ control chimeras, ß-galactosidase-negative cells were distributed in the lens epithelium as well as in other tissues (Fig. 7A,A',a). The contribution of Mab21l1-/- cells was low in 13 out of 24 Mab21l1-/- chimeras, and they appeared histologically normal. The contribution of Mab21l1-/- cells was moderate in seven out of the remaining Mab21l1-/- chimeras (Fig. 7B,C) and, although lenses were present in all of these, they were significantly smaller than normal lenses (Fig. 7A',B',C'). Importantly, considerable contribution of Mab21l1-/- cells into this small lens was not seen in any of these moderate chimeras (Fig. 7b,c). In contrast to the lens itself, a variable contribution of Mab21l1-/- cells was observed in the retina, cornea and mesenchymal tissues (Fig. 7b,c). The contribution of Mab21l1-/- cells was high in four of the Mab21l1-/- chimeras (Fig. 7D), in which no lens was formed (as in the Mab21l1-/- mutants) (Fig. 7D',d). The exclusion of Mab21l1-/- cells from the lens in chimeric mice implies that the Mab21l1 gene product acts in cell-autonomous manner during lens formation.
|
We compared the expression of Maf, Foxe3, Sox2, Six3 and Pax6 in Mab21l1+/- and Mab21l1-/- embryos at the 22-somite (E9.5) to 40-somite stages (E10.5). At the 22-somite stage, prior to lens induction, expression of PAX6 and Six3 in the Mab21l1-/- surface ectoderm did not differ from that seen in Mab21l1+/- embryos. At the 24-somite stage, upregulation of Sox2 and the first expression of Maf in the surface ectoderm occurred simultaneously in the Mab21l1-/- and Mab21l1+/- embryos. At this stage, we did not observe any significant expression of Foxe3. At the 28-somite stage, Foxe3 was clearly expressed in the Mab21l1+/- presumptive lens placode but expression was not seen in the Mab21l1-/- embryos (Fig. 8A,B). We did not find any significant difference between PAX6 expression in the surface ectoderm and optic vesicles of Mab21l1+/- embryos and Mab21l1-/- embryos (Fig. 8C,D), or any significant diferences of Maf, Sox2 and Six3 expression in the presumptive lens placode (data not shown). At the 35-somite stage, the lens placode failed to undergo sufficient invagination in the Mab21l1-/- embryo (Fig. 8F,H). Foxe3 expression was seen in the Mab21l1-/- lens placode, although its expression domain was much smaller than in Mab21l1+/- embryos and the expression level in each cell was significantly lower (Fig. 8E,F). By contrast, the level of Maf and PAX6 expression in the Mab21l1-/- lens placode was similar to that in the Mab21l1+/- developing lens pit (Fig. 8G,H; data not shown). At the 40-somite stage, expression of Foxe3 had totally disappeared in the Mab21l1-/- mutants, although a rudimentary lens placode was still present (Fig. 8I,J). Expression of Maf and PAX6 was maintained in the Mab21l1-/- lens placode as well as in the Mab21l1+/- lens vesicle. These results suggest that MAB21L1 function is required for the appropriate induction and subsequent maintenance of Foxe3 expression.
|
At the 22-somite stage, Mab21l1 expression was hardly seen in the surface ectoderm and the optic vesicle in Sey homozygous embryos, when compared with expression in wild-type littermates (Fig. 9A,B). At the 32-somite stage, Mab21l1 expression was observed at low but significant levels in both degenerated optic vesicle and the surface ectoderm in Sey homozygotes (data not shown). At the 35-somite stage, Mab21l1 expression was greatly reduced in the degenerated optic vesicles in Sey/Sey embryos when compared with the wild-type embryos (Fig. 9D). At this stage, despite the lack of lens vesicles in Sey/Sey embryos, a few overlying surface ectodermal cells expressed small amounts of Mab21l1 transcripts (Fig. 9D). In wild-type embryos, Mab21l1 was strongly expressed in the lens and presumptive neural retina (Fig. 9C). In contrast to Mab21l1, the level of Mab21l2 expression was unperturbed in the Sey/Sey embryos at all stages examined (Fig. 9E,F; data not shown). These results suggest that expression of Mab21l1 is dependent on PAX6 both in the surface ectoderm and the optic vesicle.
|
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DISCUSSION |
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Role of Mab21l1 in lens formation
Inductive interactions between the optic vesicle and the surface ectoderm
are known to be essential for induction and subsequent differentiation of the
lens placode. Signals mediated by Bmp and Fgf family proteins are essential,
converging on Pax6 expression in the lens placode
(Faber et al., 2001;
Furuta and Hogan, 1998
;
Wawersik et al., 1999
). We
found apparently normal expression of Pax6, Sox2 and Maf in
the surface ectoderm overlying the optic vesicles, which suggests that
inductive signals might not be affected in Mab21l1 mutants. However,
as noted above, our evidence suggests that MAB21L1 functions downstream of
PAX6 during lens placode development, which is consistent with the observation
that both MAB21L1 and PAX6 act in the developing lens placode in a
cell-autonomous manner (Fig. 7)
(Collinson et al., 2000
;
Quinn et al., 1996
).
We also showed that expression of Foxe3 is significantly affected
in Mab21l1-/- embryos. Foxe3 function is also
essential for lens development because it regulates the proliferation and
apoptosis of lens epithelial cells, as revealed in dyl mutants
exhibiting rudimentary lens phenotypes
(Blixt et al., 2000;
Brownell et al., 2000
;
Ormestad et al., 2002
). As
most MAB21L1 proteins are present in the nucleus in the developing lens, they
could exert transcriptional or post-transcriptional regulation of
Foxe3 (R.Y. and N.T., unpublished). Our proposal that a genetic
cascade including Pax6, Mab21l1 and Foxe3 is essentially
involved in the proliferation of lens placode cells is supported by the
observation by Dimanlig et al., who used mice harboring a targeted deletion of
the ectoderm-specific enhancer of the Pax6 gene
(Pax6
EE allele), that the resultant defect in lens
development is associated with the loss of Foxe3 expression
(Dimanlig et al., 2001
). By
contrast, the expression of Six3 in the lens placode is affected in
the Le-mutant but not in our Mab21l1-/- embryos
(Ashery-Padan et al., 2000
)
(this study), indicating that although both Six3 and Mab21l1
are regulated by PAX6, different pathways are involved.
In addition to defects in the developing lens, the
Mab21l1-/- mutants exhibit various histological
abnormalities in the cornea and anterior chamber, and both the iris and
ciliary body are absent. The developing lens is known to influence normal
development of the optic cup (Reneker et
al., 1995), and therefore the lack of the iris and ciliary body in
Mab21l1-/- mutants may be a secondary effect. However, it
is possible that Mab21l1 is intrinsically required for these tissues
because it is weakly expressed in the developing iris, ciliary body and cornea
(data not shown).
Possible compensation of Mab21l1 loss by
Mab21l2
It is interesting that defects in Mab21l1-/- mice are
restricted to the eye and preputial gland even though the transcripts are also
found in the midbrain, branchial arch, spinal cord and limb buds. It is
presumed that this relatively mild phenotype in Mab21l1-/-
mice might be caused by compensation by the closely related gene product
MAB21L2, which exhibits very similar expression during development except in
the developing lens and the primordium of reproductive organs
(Mariani et al., 1999;
Mariani et al., 1998
;
Wong et al., 1999
) (R.Y. and
N.T., unpublished). Intriguingly, Mab21l2-/- mutants
exhibit much stronger defects in various tissues than
Mab21l1-/- mutants, and die in the mid-gestational stage.
It is presumed that MAB21L1 cannot fully compensate for Mab21l2
deficiency because the mutant embryos exhibit abnormalities in tissues where
there is overlapping expression (R.Y. and N.T., unpublished). This could
explain the phenotypical differences between our
Mab21l1-/- mutants and previous loss-of-function embryos
generated using an antisense ODN approach
(Wong and Chow, 2002a
). The
latter mutants exhibit failure of embryonic turning and neural tube closure as
well as eye defects. A slight reduction in MAB21L2 or an unpredicted depletion
of other genes by Mab21l1-specific ODN could modify the phenotype
caused by Mab21l1 depletion.
Male and female sterility in Mab21l1 mutants
We also found a defect in the accessory reproductive organs, with
malformation of the preputial gland in Mab21l1-/- adult
males. Importantly, most Mab21l1-/- mice of both sexes
were sterile; however, in vitro fertilization experiments revealed that the
germ cells were normal (T.H. and H.K., unpublished). This suggests that
infertility in Mab21l1-/- mice could be caused by defects
in the preputial gland and/or by behavioral changes. Blindness per se is not
responsible because another eye mutant, aphakia (Pitx3
Mouse Genome Informatics), is fertile
(Semina et al., 2000). By
contrast, homozygous spdh-mutant male mice harboring a spontaneous
mutation in the Hoxd13 gene lack preputial glands and are sterile,
whereas the females exhibit normal fertility
(Johnson et al., 1998
). The
difference between spdh/spdh males and females reflects the
dispensable role of the preputial gland in females. The fact that
Mab21l1-/- mice of both sexes are infertile with only
incomplete loss of the preputial gland, indicates that some other factors may
also be contributory. Sexual behavior could be affected in
Mab21l1-/- mice for either of the following reasons.
First, the preputial gland in male mice has been shown to contribute to
pheromonal function: generating chemosignals that attract females and
accelerating oestrus (Bronson and Caroom,
1971
; Chipman and Albrecht,
1974
). Second, the localization of Mab21l1 transcripts
within the CNS is consistent with studies that link reproductive behavior to
specific regions of the brain, collectively known as the vomeronasal system
(VNS) (Segovia and Guillamon,
1993
). We identified Mab21l1 expression in the VNS, which
includes the vomeronasal organ (VNO), accessory olfactory bulb, amygdala and
hypothalamus (R. Y., unpublished). The VNO is a chemoreceptive organ that is
thought to mediate pheromone effects
(Halpern, 1987
). Importantly,
Mab21l2 appears not to be expressed in the VNS, except in the
hypothalamus. Although we could not find any histological alterations in the
VNS, it is possible that reproductive behavior could be profoundly affected in
Mab21l1-/- mice.
Evolutional conservation of a genetic pathway including MAB21
family
The MAB21 family is highly conserved and orthologs are found from C.
elegans to humans (Mariani et al.,
1999; Wong and Chow,
2002b
). Several experiments have shown the importance of members
during development in the nematode, zebrafish, Xenopus and mouse
(Chow et al., 1995
;
Kawahara et al., 2002
;
Kudoh and Dawid, 2001
;
Lau et al., 2001
;
Wong and Chow, 2002a
). In
C. elegans, mab-21 may modulate the functions of egl-5, an
ortholog of Drosophila Abdominal B (Abd-B), and
mab-18, a Pax6 ortholog, during the specification of ray
identity (Chow and Emmons,
1994
; Chow et al.,
1995
). In addition, mab-21 has been shown to act
downstream of the TGF-ß signaling pathway leading to the male tail
morphogenesis (Morita et al.,
1999
). The present report provides evidence that Mab21l1
and Pax6 lie in the same genetic pathway involved in vertebrate eye
development. The signaling axis TGF-ß/mab-18/mab-21 in C.
elegans is reminiscent of the Bmp7/Pax6/Mab21l1 axis implicated
in lens development of mice. However, we cannot explain functional roles
because of a lack of knowledge of common denominators in ray and eye
morphogenesis.
However, the abnormal preputial gland formation in
Mab21l1-/- males is also seen in spdh
homozygotes, a Hoxd13 mutant
(Johnson et al., 1998). As
both egl-5 and Hoxd13 are Drosophila Abd-B
orthologs (de Rosa et al.,
1999
), similar genetic cascades including egl-5/mab-21 or
Hoxd13/Mab21l1 could operate in ray identity specification and
preputial gland formation, respectively. Therefore, during mammalian lens and
preputial gland development, Mab21l1, Hoxd13 and Pax6 may
have a regulatory relationship that resembles that of the mab-21,
egl-5 and mab-18 genetic pathway in C. elegans ray
development. Further studies are required to understand the molecular
functions of the MAB21 family members that contribute to the morphogenesis of
various tissues across species.
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ACKNOWLEDGMENTS |
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