1 Department of Biochemistry and Molecular Biology, University of Texas, M.D.
Anderson Cancer Center, Houston, TX 77030, USA
2 Program in Genes and Development, Graduate School of Biomedical Sciences
(GSBS), University of Texas-Houston, Health Sciences Center and M.D. Anderson
Cancer Center, Houston, TX 77030, USA
3 Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030,
USA
4 Department of Genetics, St Jude Children's Research Hospital, Memphis, TN
38105, USA
5 Departments of Molecular, Cell and Developmental Biology, Orthopedic Surgery,
and Biological Chemistry, University of California, Los Angeles, CA 90095,
USA
6 Laboratory of Reproductive and Developmental Toxicology, National Institute of
Environmental Health and Safety/NIH, Research Triangle Park, NC 27709,
USA
Author for correspondence (e-mail:
yfuruta{at}mdanderson.org)
Accepted 22 December 2004
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SUMMARY |
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Key words: Bmpr1a, Bmpr1b, Bmp signaling, Mutant mouse, Retinal patterning, Retinal growth, Retinal neurogenesis
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Introduction |
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Within the optic cup, Bmp signaling mediated by the dorsally localized Bmp4
ligand appears to control the patterning of the dorsoventral axis of the
developing retina. Ectopic expression of Bmp4 in the embryonic chick
retina leads to the upregulation of the dorsal transcription factor,
Tbx5, throughout the optic cup, and downregulation of the ventral
markers, Vax and Pax2
(Koshiba-Takeuchi et al.,
2000). Bmp4 signaling may be subject to negative regulation by the
ventrally localized Bmp4 antagonist, ventroptin (Chrdl1 - Mouse Genome
Informatics) (Sakuta et al.,
2001
). Forcing dorsal expression of ventroptin in the early chick
retina represses dorsal Bmp4 expression and expands Vax
expression. These molecular changes result in severely abnormal projection
patterns of retinal ganglion cell axons. Bmp signaling has also been
implicated in other aspects of retinal development. Bmp4 can influence
proliferation and cell death in the chick retina
(Trousse et al., 2001
).
Inhibition of Bmp signaling in the chick retina by overexpression of the Bmp
antagonist, Noggin, leads to disruption of ventral retinal structures
(Adler and Belecky-Adams,
2002
). At present, however, the possible involvement of Bmp
signaling in retinal cell differentiation in vertebrates has not been
established, whereas the Bmp homolog decapentaplegic (Dpp)
is a principal regulator of retinal neurogenesis in Drosophila.
Several Bmp ligands and cognate receptors are expressed in the developing
mouse eye (Dudley and Robertson,
1997
; Furuta and Hogan,
1998
). One possible model to account for the diverse effects of
Bmps in the eye is that the different ligand-receptor combinations can result
in qualitative differences in signaling output. Alternatively, different
developmental processes may require distinct levels of signaling activity as
described in a morphogen model (Freeman
and Gurdon, 2002
).
The Bmp ligands signal via heteromeric complexes composed of type I and
type II transmembrane serine/threonine kinase receptors
(Mishina, 2003). In the
ligand-activated complex, the type II receptors phosphorylate and activate
type I receptors. Activated type I receptors in turn trigger downstream
signaling by Smad proteins, which are responsible for transduction of the
extracellular signal to the nucleus. In this system, the activity of type I
receptors primarily dictates the level and specificity of the intracellular
signaling. Among various type I receptors, Acvr1 (Alk2), Bmpr1a (Alk3) and
Bmpr1b (Alk6) are capable of mediating Bmp ligand signal, although the
affinity for different ligands varies among these receptors
(Mishina, 2003
). Of these,
Bmpr1a and Bmpr1b are expressed within the developing mouse
retina (Furuta and Hogan,
1998
). Sources of Bmp ligand that can potentially signal to the
retina via Bmpr1a and/or Bmpr1b include Bmp7 in the lens and peri-ocular
mesenchyme, Bmp4 in the dorsal retina, and Bmp2 and Bmp3 in the retinal
pigment epithelium and surrounding mesenchyme, respectively
(Dudley and Robertson, 1997
;
Furuta and Hogan, 1998
;
Wawersik et al., 1999
). In
order to resolve this complex signal transduction apparatus, it is crucial to
evaluate the cell type specific roles of the signaling pathway in vivo.
Moreover, although multiple receptor-ligand pairs have been suggested to exist
by biochemical experiments, genetic evidence for redundancy among the various
receptors is lacking.
Here, we report the generation of retina-specific Bmp type I receptor mutant mice to investigate the role of Bmp signaling within the developing retina. A graded diminution of Bmp signaling activity, achieved by combining mutations of Bmpr1a and Bmpr1b genes causes defects in multiple aspects of retinal development, including dorsoventral patterning, growth and differentiation. Our studies provide direct genetic evidence that Bmpr1a and Bmpr1b play largely redundant roles during early retinal development, and that different thresholds of Bmp signaling regulate distinct developmental programs in the retina.
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Materials and methods |
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Tissue preparations for marker analyses
Embryonic tissue explant culture using filters and BMP4-soaked beads was
performed essentially as described (Furuta
and Hogan, 1998). Recombinant human BMP4 protein was kindly
provided by the Genetics Institute (Cambridge, MA). Embryos or cultured
explants were fixed in 4% paraformaldehyde in PBS, dehydrated through a graded
series of methanol, followed by whole-mount in situ hybridization (see below)
or histological sectioning. Sections were processed for Hematoxylin and Eosin
staining, in situ hybridization or immunohistochemistry (see below). For
analyses of retinal cell type markers, fixed retinal tissues were embedded in
polyester wax (Electron Microscopy Sciences, PA) for sectioning. For all the
experiments described here, three or more animals/embryos of each genotype
were examined.
In situ hybridization
In situ hybridization using [35S] UTP-labeled riboprobes on
sections or digoxigenin (DIG)-labeled riboprobes on sections or whole-mount
embryos was performed essentially as described previously
(Nagy, 2003). Templates for
Rldh1a1, Rldh1a3, Chx10, Brn3b and Math5 (Atoh7 -
Mouse Genome Informatics) RNA probes were obtained from a retinal EST library
(Mu et al., 2001
). Photos for
radioactive in situ sections were taken by double exposures, digitally
combining dark field images under a red channel and bright-field images under
a blue channel. Pictures for DIG in situ sections were photographed under
differential interference contrast illumination.
Immunohistochemistry
Antibodies used for immunohistochemical detection were anti-Syntaxin
monoclonal antibody (mAB) (HPC-1, Sigma), anti-ß-tubulin III mAB (TU-20,
Chemicon International),
anti-phospho-smad1(ser463/465)/smad5(ser463/465)/smad8(ser426/428) rabbit
polyclonal (Cell Signaling Technologies), anti-cyclinD1 mAb (Santacruz
Biotechnology) and rabbit antisera to protein kinase C- (Sigma).
Secondary antibodies were biotin conjugated anti-mouse IgG (goat),
Cy2-conjgated anti-rabbit IgG and Cy3-conjugated anti-mouse IgG (Jackson
Immuno Research Laboratories) in appropriate combination with primary
antibodies. For detection of biotin-conjugated antibodies, specimens were
incubated with peroxidase-conjugated streptoavidin (Vectastain ABC kit; Vector
Laboratories), followed by chromogenic reactions using diaminobenzidine (0.6
mg/ml in 50 mM Tris-Cl, pH=7.6) as a substrate in the presence of 0.03%
H2O2.
Analyses for cell proliferation and cell death
Pregnant mice were injected intraperitoneally with 1 ml/100 g body weight
of Cell Proliferation Labeling Reagent (Amersham) 2 hours before embryo
dissection. Sections of BrdU-labeled embryos were processed for
immunohistochemical analysis using an anti-BrdU monoclonal antibody (Chemicon
International). A biotin-conjugated anti-mouse secondary antibody, bound by
extravidin-FITC was used for fluorescence detection. BrdU-positive cells were
counted manually, and expressed as a percentage of total cell number. TUNEL
apoptosis detection was performed using Apoptag Cell Death Detection Kit
(Chemicon International) according to the manufacturer's instructions.
Retinotopic mapping analyses
Anesthetized P7-P10 pups were injected with DiI (Molecular Probes) applied
focally to dorsal or ventral region of the retina using a Nanoject (Drummond).
For each labeling, 9.2 nl of 10% DiI dissolved in dimethyl formamide was
injected. The brain of labeled pups was dissected 2 days after injection. The
superior colliculus was exposed by removing cerebral hemispheres, observed and
photographically documented under fluorescent stereoscopes.
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Results |
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Animals lacking retinal Bmpr1a function (Bmpr1a-/fx in the Six3Cre transgenic background; referred to as Bmpr1a-/fx;Cre below) develop normally without overt ocular abnormalities. In the adult retina, the characteristic layered structure is retained in the mutant (Fig. 1A), without significant qualitative changes in the distribution of major retinal cell types examined (data not shown). Bmp signaling is implicated in dorsoventral patterning of the retina, which is reflected later in the retinotectal projection maps formed by retinal ganglion cell axons. We analyzed the trajectory of retinal ganglion cell axons from the retina to the superior colliculus (mid-brain) using focal injection of the lipophilic dye, DiI. In wild-type mice, dorsal retina-derived ganglion cell axons project to the lateroposterior quadrant of the contralateral mid-brain (e.g. Fig. 1B, left) and ventral ganglion cell axons, to the medioanterior domain (not shown). In the mutants, the dorsal axons project to their termination zones in a wild-type pattern, suggesting that retinotectal projections are unaffected (Fig. 1B, right). Genomic PCR analyses confirm extensive Cre-mediated recombination of the Bmpr1afx allele throughout the differentiated retina in the adult (Fig. 1C,D), suggesting that the retina of Bmpr1a conditional mutants is entirely composed of Bmpr1a-deficient cells. As discussed below (Fig. 3), loss of Bmpr1a function appears to take place early during retinal development. Therefore, we conclude that Bmpr1a function is not essential for gross patterning, morphogenesis and differentiation of the developing retina.
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The retinoic acid signaling pathway is also implicated in the regulation of
retinal dorsoventral patterning (Hyatt et
al., 1996; Marsh-Armstrong et
al., 1994
; McCaffery et al.,
1999
). Genes coding for enzymes regulating retinoic acid
synthesis, including Rldh1a1 for Raldh1 and Rldh1a3 for
Raldh3, are differentially expressed along the dorsoventral axis of the retina
(Fig. 4A,C). It has been
suggested that the differential expression of these genes along this axis may
be regulated by a Bmp4-Tbx5 pathway (Mic
et al., 2002
). However, the expression of these genes appears
unaffected in
Bmpr1a-/fx;Bmpr1b+/-;Cre
mutants (Fig. 4B,D).
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Bmp signaling is required for the expression of Fgf15 in the developing retina
Fibroblast growth factors constitute another class of secreted signaling
molecules that have potential functions in retinal development (see
Discussion). These include the regulation of cell survival and proliferation,
as well as retinal neurogenesis. As these processes are affected in the Bmp
receptor mutants, it is possible that Fgfs act as mediators of Bmp signaling
in this regard. One of the Fgf family members expressed specifically within
the optic vesicle is Fgf15
(McWhirter et al., 1997). In
wild-type embryos, the expression of Fgf15 initiates at around the
15-somite stage (not shown), a few hours following the onset of Bmp4
expression in the prospective retinal neuroectoderm. Fgf15 expression
is upregulated subsequently, and persists throughout embryonic retinal
development (not shown). First, to determine whether the Fgf15
expression is dependent on Bmp signaling, we examined
Bmp4-/- mutant embryos for Fgf15 transcripts. In
the absence of Bmp4, Fgf15 expression is drastically reduced or
absent in the optic vesicle (Fig.
7B). Furthermore, in explant cultures, the expression of
Fgf15 can be restored by exposure of the optic vesicle of
Bmp4-/- mutants to Bmp4 protein carried by beads
(Fig. 7C). Consistent with
these observations, the expression of Fgf15 is diminished in the
retina of
Bmpr1a-/fx;Bmpr1b-/-;Cre
double mutants at E11.5 (Fig.
7E,F). Thus, Bmp signaling largely mediated by Bmp4 is essential
to induce the expression of Fgf15 in the early developing retina.
Bmp4 cannot induce Fgf15 expression in the retinal pigmented
epithelium, suggesting that this regulation may be permissive rather than
instructive.
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Discussion |
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Bmpr1a and Bmpr1b play redundant roles during retinal development
Our studies provide the first direct genetic evidence for functional
redundancy between the two Bmp type I receptors, Bmpr1a and Bmpr1b. These two
receptors share a high degree of sequence similarity and are both capable of
binding to Bmp2, Bmp4 and Bmp7 ligands, albeit with varying affinities
(Mishina, 2003). However,
previous studies indicate that they may possess distinct biological functions.
A study using forced expression of constitutively active Bmpr1a and Bmpr1b
receptors, both in transgenic mice and in neural stem cells, suggested a role
for Bmpr1a in regulating proliferation in the developing central nervous
system and for Bmpr1b in regulating apoptosis and terminal differentiation
(Panchision et al., 2001
).
Similarly, in chick limb bud development, ectopic expression of constitutively
active and dominant-negative forms of the two receptors revealed a role for
Bmpr1b in mediating formation of the initial cartilaginous skeleton, and for
Bmpr1a in controlling the later differentiation process
(Zou et al., 1997
). However,
during chick neural tube patterning, expression of constitutively active forms
of the two receptors revealed no significant qualitative differences in the
cellular responses (Timmer et al.,
2002
). The apparent discrepancies in these studies may be
attributable, in part, to differences in the experimental models and tissue or
cell types examined. With respect to the phenotypes described here, the lack
of retinal abnormalities in the conditional Bmpr1a null mutants or
Bmpr1b mutants in comparison with the Bmpr1a/Bmpr1b
double null mutant retina indicates the functional redundancy between the two
receptors in vivo. One broad implication of the current study is that
Bmpr1a and Bmpr1b may also play redundant roles in other
tissues. For example, analysis of Bmpr1a function in the embryonic
telencephalon revealed its requirement only in the dorsal midline, a domain
where Bmpr1b is not expressed, unlike the more lateral telencephalic
regions where the expression of Bmpr1a and Bmpr1b overlap
(Hebert et al., 2002
). Thus,
it is likely that disruption of both receptors in the telencephalon may reveal
a more extensive requirement for Bmp signaling. Furthermore, this general
principle may be extended to receptors for other subgroups of the TGFß
superfamily ligands. For example, canonical TGFß ligands can bind to both
Tgfbr1 (Alk5) and Acvrl1 (Alk1), and activins can bind to Acvr1b (Alk4) and
Acvr1 (Alk2). We do note that the degree of functional overlap between
Bmpr1a and Bmpr1b may vary depending on the developmental
context, For example, within the eye itself, optic nerve head axonal guidance
may require only Bmpr1b function
(Liu et al., 2003
).
Dorsoventral patterning defects are present in
Bmpr1a-/fx;Bmpr1b+/-;Cre, but not in
Bmpr1a+/fx;Bmpr1b-/-;Cre
mutants, suggesting that the two receptors are not completely equivalent. Such
differences could arise from varying temporal/spatial expression domains,
levels of expression and/or biochemical properties.
Bmp signaling is necessary for the patterning of the retinal dorsoventral axis
The requirement for Bmp signaling in dorsal retina specification is
analogous to its role in dorsal neural tube patterning and dorsal forebrain
differentiation in vertebrates (Furuta et
al., 1997; Hebert et al.,
2002
; Timmer et al.,
2002
), suggesting that this function is conserved in different
parts of the developing nervous system. One potential implication is a
conservation of the underlying genetic mechanisms, such as interactions with
the Shh-mediated patterning activity that occurs in the developing neural
tube. In the chick optic vesicle, reducing endogenous Shh activity results in
an expansion of Bmp4 expression
(Zhang and Yang, 2001
),
suggesting opposing roles of Bmp and Shh signaling in retinal dorsoventral
patterning.
Our study has identified the bona fide receptors that mediate the Bmp
signaling in retinal dorsoventral patterning. The genetic evidence presented
in this study indicates that the dorsal Bmp signal intersects with the ventral
pathway at the level of or upstream of Vax2 expression
(Fig. 8D). In Vax2
mutants, Tbx5 expression, a downstream readout of Bmp signaling, is
unaffected (Barbieri et al.,
2002; Mui et al.,
2002
), whereas loss of Tbx5 expression in
Bmpr1a-/fx;Bmpr1b+/-;Cre
mutant animals results in expansion of the Vax2-positive domain. In
the Bmp receptor mutant animals, asymmetric expression patterns of
Bmp4 and Bmpr1b appear unaffected (data not shown),
suggesting that Bmp signaling is one of the most upstream events in dorsal
retinal cell fate specification. Taken together, one possible model is that
the ventral program is a default state, and Bmp signaling provides the
instruction to initiate the dorsal program. Although the mechanisms underlying
the gradient expression patterns of Eph-Ephrin molecules remain unclear, the
Bmpr1a-/fx;Bmpr1b+/-;Cre
mutant animals, as well as Vax2-null mice
(Barbieri et al., 2002
;
Mui et al., 2002
), will
provide useful genetic tools for future investigations of topographic map
formation.
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Bmp signaling regulates cell survival during retinal growth
Bmps have been implicated in the regulation of cell proliferation and cell
death in various developmental contexts, including the developing retina
(Trousse et al., 2001). The
current genetic studies have uncovered potential downstream effectors of Bmp
signaling in these processes. In the
Bmpr1a-/fx;Bmpr1b-/-;Cre
double homozygous mutants retinal structures are specified initially, but cell
proliferation and cell death are severely affected during mid-gestation. A
previous study has shown that Chx10 and cyclin D1, two genes whose
expression is affected in the double mutants, may have a regulatory
relationship in the retina (Chang et al.,
2003
). The phenotypes of individual homozygous mutants for
Chx10 and cyclin D1 include microphthalmia and photoreceptor
degeneration, respectively (Burmeister et
al., 1996
; Sicinski et al.,
1995
); however, most retinal neurons are present in the eye of
these mutants. The
Bmpr1a-/fx;Bmpr1b-/-;Cre
double null mutant phenotype is more severe possibly due to the combinatorial
loss of Chx10 and cyclin D1.
The
Bmpr1a-/fx;Bmpr1b-/-;Cre
double mutants show increased levels of apoptosis from E11.25, possibly owing
to a lack of survival signals to the retinal progenitor cells. Although Bmps
themselves may act as survival factors in the eye, fibroblast growth factors
are also candidate mediators of Bmp signaling in this regard. Within the eye,
they are expressed in the surface ectoderm (Fgf1, Fgf2), the
neuroretina (Fgf15, Fgf9) (Nguyen
and Arnheiter, 2000; Zhao et
al., 2001
) and the central retina-optic stalk region
(Fgf8) (Chow and Lang,
2001
). Several studies have implicated Fgfs in the specification
and survival of the neuroretina (Lillien
and Cepko, 1992
; Park and
Hollenberg, 1989
; Pittack et
al., 1997
). Fgf signal transduction per se may operate through the
Ras/Mapk or the PI-3 kinase/Akt pathway, which, in turn, are known to regulate
cell survival by transcription-dependent and -independent inhibition of
apoptosis (Brunet et al., 2001
;
Powers et al., 2000
). Thus,
the loss of Fgf15 signaling may, in part, contribute to retinal degeneration
resulting from apoptosis in the
Bmpr1a-/fx;Bmpr1b-/-;Cre
double mutants.
A novel role for Bmp signaling in retinal neurogenesis
Despite well-characterized roles of signaling molecules, including hedgehog
(Hh) and Dpp, in Drosophila retinal neurogenesis, the signaling
events upstream of mouse retinal neurogenesis remain elusive. In particular,
the requirement of Hh in retinal ganglion cell specification (i.e. induction
of atonal homologs) is unclear
(Stenkamp and Frey, 2003).
Analysis of
Bmpr1a-/fx;Bmpr1b-/-;Cre
double mutants has revealed a novel function for Bmp signaling in retinal
neurogenesis. Although we observe abnormal neuronal tubulin expression in the
E12.5 double mutant retina, these labeled cells are not positive for early
pro-neural genes such as Math5
(Fig. 6) and Neurod1
(data not shown), or for neurofilament (data not shown). The rapid
degeneration of the double mutant retina subsequent to E12.5 precludes
analysis of later-born neurons. We therefore conclude that Bmp signaling is
required for early neurogenesis in the mouse retina. This is in contrast to
the observation that initiation of neurogenesis and expression of
atonal in the Drosophila eye can occur in the absence of Dpp
signaling (Fu and Baker,
2003
). Given that Pax6 expression is maintained in the
absence of neurogenesis, it is likely that Bmp signaling intersects with the
Pax6-mediated pathway to initiate differentiation of retinal progenitor cells.
In this context too, the effects of Bmp signaling on pro-neural gene
expression may involve an Fgf receptor-Ras/Mapk signal. Exogenous FGFs are
reported to be capable of inducing ganglion cell markers in retinal explants
(Guillemot and Cepko, 1992
).
This model is also analogous to that in Drosophila where the
Egfr-Raf-Mapk pathway has been implicated in the induction of atonal
(Greenwood and Struhl, 1999
;
Kumar and Moses, 2001
). There
also remains the possibility that this abnormality in retinal differentiation
is tightly coupled to the decreased growth in the mutant retina
(Fig. 8E). The possible
causative regulatory relationships between these multiple developmental
processes are the subject for future studies.
Different threshold requirements for Bmp signaling in various aspects of retinal development
Our in vivo genetic analysis has generated novel insights regarding the
mechanisms by which Bmp signaling regulates various aspects of retinal
development. Given the range of Bmp ligands and receptors expressed in the
developing retina (Fig. 8A,B),
in principle, potentially distinct signaling properties of individual ligands
and receptors may underlie different cellular responses. Our data are more
consistent with an alternative model wherein different aspects of retinal
development, such as patterning and morphogenesis, are regulated at distinct
threshold levels of Bmp signaling input
(Fig. 8D,E). Our results
strongly indicate the existence of at least two threshold levels of Bmp
signaling. First, specification of the dorsal retina requires relatively high
levels of Bmp signaling that cannot be maintained by only one functional
allele of Bmpr1b (Fig.
8D). The observations that the wild-type dorsal retina expresses
high levels of both Bmp4 ligand (Furuta
and Hogan, 1998) and P-smad protein
(Fig. 3D) corroborate this
idea. Second, complete elimination of the function of both Bmpr1a and Bmpr1b
receptors in double null mutants leads to catastrophic effects in the
developing retina, including defects in retinal proliferation and retinal
neurogenesis. These data suggest the presence of a lower threshold of
signaling throughout the retina that can maintain overtly normal retinal
morphogenesis and differentiation in the
Bmpr1a-/fx;Bmpr1b+/-;Cre or
Bmpr1a+/fx;Bmpr1b-/-;Cre
mutants. A recent study using Noggin overexpression in chick has shown a
requirement for Bmp signaling in the development of the ventral optic cup
(Adler and Belecky-Adams,
2002
). In these experiments, inhibition of Bmp signaling resulted
in a range of abnormalities, including microphthalmia, ventral retinal
colobomas, altered expression of dorsoventral markers and optic nerve
pathfinding defects similar to those reported for the
Bmpr1b-/- mutants (Liu
et al., 2003
). These ventral retina defects may represent a
phenotype intermediate between the dorsoventral patterning defects and the
retinal degeneration described in our system, indicating possible existence of
a third threshold of Bmp signaling during retinal development. The mechanisms
by which individual cells divide the overall receptor-mediated signaling into
graded units of activities and assign them to elicit qualitatively distinct
genetic programs may have implications for other growth factor signaling
systems.
Note added in proof
During the review of our revised manuscript, a study revealing redundant
roles of Bmpr1a and Bmpr1b in the developing mouse neural tube was published
(Wine-Lee et al., 2004).
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ACKNOWLEDGMENTS |
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Footnotes |
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