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DEVELOPMENTAL DYNAMICS 208:526–535 (1997)
Characterization of the Fate of Midline Epithelial Cells
During the Fusion of Mandibular Prominences In Vivo
YANG CHAI,1 YASUYUKI SASANO,1 PABLO BRINGAS, JR.,1 MARK MAYO,1 VESA KAARTINEN,2
NORA HEISTERKAMP,2 JOHN GROFFEN,2 HAROLD SLAVKIN,3 AND CHARLES SHULER1*
1Center for Craniofacial Molecular Biology, School of Dentistry, University of Southern California, Los Angeles, California
2Department of Pathology, Surgery and Pediatrics, Childrens Hospital of Los Angeles Research Institute,
Los Angeles, California
3Craniofacial Development Section, National Institute of Arthritis and Musculoskeletal and Skin Disease,
National Institute of Health, Bethesda, Maryland
ABSTRACT
The fusion of the mandibular
prominences along the midline is achieved with
the absence of medial epithelial cells at the fusion
site. Failure of fusion of the mandibular prominences results in median cleft of the lower lip and
mandible. Cellular and molecular events controlling mandibular fusion were examined during
the fusion process in mouse embryogenesis. Cell
lineage analyses at the fusion site revealed that
epithelial cells migrated to the surface and oral
epithelia. DiI-labeled epithelial cells were not
observed within the mandibular mesenchyme at
any stage of fusion. Examination of the midline
region did not reveal cells with ultrastructural
changes characteristic of apoptotic cell death. An
increase in lysosomal enzymes in the midline
epithelial cells, which would be correlated with
programmed cell death, was not observed. Mice
lacking TGF-b3 did not have cleft mandible, but
had clefting of the secondary palate as a feature
of null mutation phenotype. We interpret our
comparisons between wild type and homozygous
TGF-b3 (2/2) mice to suggest that different developmental processes control palatal vs. mandibular fusion. We hypothesize that medial epithelial
cells at the fusion site of mandibular prominences migrate to the surface epithelium during
the fusion process and neither transdifferentiate
into mesenchyme nor express apoptosis. Dev. Dyn.
208:526–535, 1997. r 1997 Wiley-Liss, Inc.
Key words: mandible; morphogenesis; medial epithelial cells; TGF-b3 null mutation
INTRODUCTION
First branchial arch syndromes constitute a major
proportion of craniofacial anomalies. These anomalies
are the result of altered development of first arch
derived structures such as palate, maxilla, and mandible. Although not common, several syndromes with
mandible dysmorphogenesis (e.g., mandibular dysplasia, mandibulofacial dysostosis) have been described
(Jones, 1988; Gorlin et al., 1990). Clinically, sporadic
cases of median clefts of the lower lip and mandible
have also been reported. The vertebrate facial morphor 1997 WILEY-LISS, INC.
genesis requires five prominences to fuse according to
exquisite time and positional information: (1) frontonasal prominence, (2) paired maxillary prominences, and
(3) paired mandibular prominences. Median clefts of
the lip and mandible result from a failure of fusion of
the first branchial arch derived paired mandibular
prominences, and/or failure of mesenchymal cell penetration into the midline. The severity of the mandibular cleft defects depends upon the developmental stage
at which the fusion of mandibular prominences was
disturbed (Oostrom et al., 1996). Significantly, the
cellular, molecular, and developmental processes controlling fusion of mandibular prominences have not
been determined.
Complete fusion of the mesenchymal portion of the
mandibular prominences requires the absence of a
distinct epithelial component in the midline. In studies
of medial edge epithelial (MEE) cell fate during palatal
fusion, three different mechanisms have been proposed
to account for the disappearance of the MEE from the
midline position of the forming secondary palate. First,
a long-standing hypothesis proposed that disappearance of MEE cells was a result of classical programmed
cell death (Shapiro and Sweney, 1969; Pratt and Martin, 1975; Pratt et al., 1984; Clarke et al., 1993). Second,
another hypothesis for the fate of the MEE stated that
MEE cells underwent an epithelial-mesenchymal transformation and remained in the connective tissue of the
secondary palate as viable mesenchymal cells (Fitchett
and Hay, 1989; Griffith and Hay, 1992; Shuler et al.,
1991, 1992; Shuler, 1995). Third, yet another hypothesis suggested that MEE cells retained both their
viability and epithelial phenotype and migrated from
the fusion midline position to join with either adjacent
oral or nasal epithelia (Carette and Ferguson, 1992). A
similar process may have a function in the disappearance of the epithelial cells from the midline of the fusing
mandibular prominences.
*Correspondence to: Dr. Charles Shuler, Center for Craniofacial
Molecular Biology, School of Dentistry, University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA 90033.
Received 17 October 1996; Accepted 8 January 1997
FUSION OF MANDIBULAR PROMINENCES
527
To test the hypothesis that midline epithelial cell fate
is neither epithelial-mesenchymal transformation nor
apoptosis, we designed studies to examine the process
of mandibular fusion during embryogenesis. The fate of
epithelial cells at the midline of fusion were examined
for evidence of programmed cell death, epithelialmesenchymal transformation, and epithelial cell migration. The results of these studies support the hypothesis that the developmental processes required for the
fusion of mandibular prominences are significantly
different than those required for secondary palate
formation.
RESULTS
Three Stages of Mouse Embryogenesis and
Mandibular Prominence Fusion
Mandibular prominence fusion starts at E9.5 when
the first branchial arch-derived, paired mandibular
prominences approximate one another at the midline.
Macroscopic orientation of whole mouse embryos and
histology of mandibular morphogenesis from E9 through
E11 are shown in Figures 1 and 2. Inspection of
timed-pregnant mouse embryos indicated that the fusion of mandibular prominences was completed within
24–36 hr. At E11, 36 hr after the beginning of mandibular fusion, the mandible is completely fused at the
midline. Histological evaluation revealed that midline
epithelium was intact and two cell layers thick at E9
(Fig. 2A). At E9.5, the opposing medial epithelia were
adherent at the midline, which marked the beginning of
the fusion process (Fig. 2B). Twelve hours later, at E10,
the opposing mandibular epithelia united by forming
an epithelial cell mass 3 to 4 cell layers thick (Fig. 2C).
Early disruption of midline epithelium was observed at
E10.5 (Fig. 2D). Epithelial triangles at the two external
surfaces were found in the mandibular prominences at
E10.5 and E11. By E11, the fusion was complete with
mesenchymal confluence across the midline and the
absence of epithelial islands (Fig. 2E).
Scanning electron microscopy (SEM) was used to
examine the developmental stages of mandibular prominence fusion (Fig. 3). At E9 to E9.5, the opposing
mandibular prominences came in close approximation
(Fig. 3A,B). At E10, the external surfaces of the paired
mandibular prominences were beginning to merge (Fig.
3C). Mandibular fusion was completed at E11 (Fig. 3D).
Apoptosis Was Not Observed at the Mandibular
Prominence Fusion Site
At E10, a thick epithelial cell mass (3–4 layers thick)
was seen at the fusion site in serial thin sections of the
mandible (Fig. 4A). Interruption of extracellular matrix
occurred as the fusion process was initiated (Fig. 4B,C).
On adjacent sections from the same mandibular prominence, complete separation of oral and suboral epithelium was evident (Fig. 4D). Transmission electron
Fig. 1. Embryonic mouse morphogenesis in vivo. A: Lateral view of
E9 (13–20 somite pairs, Theiler stage 14) mouse embryo, which showed
mandibular prominence (m). B: Lateral view of E10 (30–34 somite pairs,
Theiler stage 16) mouse embryo, which showed both mandibular and
maxillary (mx) prominences. C: Lateral view of E11 (40–44 somite pairs,
Theiler stage 18) mouse embryo. Scale bar 5 1 mm.
528
CHAI ET AL.
Fig. 2. Histological sections of mandibular prominences at the fusion
site. A: At E9, the midline epithelium (me) was intact and two cell layers
thick at the midline. B: At E9.5, the opposing medial epithelia were
adherent at the midline (arrow). C: At E10, the opposing mandibular
epithelia united by forming an epithelial cell mass 3 to 4 cell layers thick
(arrow). D: At E10.5, early disruption of midline epithelium was observed
(arrow). Epithelial triangles (double arrow) at the two external surfaces
were found in the mandibular prominences. E: By E11, the fusion was
complete with mesenchymal confluence across the midline and the
absence of epithelial islands. Scale bar 5 100 µm.
microscopy examination did not reveal intracellular
changes characteristic for apoptosis in the epithelium
at the mandibular fusion site (not shown).
Another line of evidence commonly used to support
‘‘programmed cell death’’ as the mechanism for the
disappearance of MEE in secondary palatal fusion, is
FUSION OF MANDIBULAR PROMINENCES
529
the observation of increased lysosome activity in the
midline seam (Mato et al., 1966). Lysosomal activity
was noted, albeit faint, in the midline epithelium at the
fusion site (Fig. 5). At E10, the midline seam was
interrupted by mesenchymal cells, and the epithelial
triangle and contacting midline epithelium showed a
slight increased lysosomal activity (Fig. 5A,B). On
completion of mandibular fusion at E11, lysosomal
staining was present in only a limited area of oral
surface epithelium (Fig. 5C,D). There was no lysosomal
activity observed in the mesenchymal cells adjacent to
the midline during the mandibular fusion. The absences of ultrastructural changes and lysosomal activity are not consistent with a programmed cell death or
an apoptotic cell fate for the midline epithelia associated with mandibular prominence fusion.
Mandibular Prominence Midline Epithelial
Cells Did Not Transdifferentiate Into
Mesenchymal Cells
Fig. 3. Scanning electron microscopy showed the fusion stages of mouse
mandibular prominences. A: At E9, the opposing mandibular prominences (m)
came in close approximation. B: At E9.5, there was a broad contact between
left and right mandibular prominences (arrow). C: At E10, the external surfaces
of the paired mandibular prominences were beginning to merge. D: At E11,
mandibular fusion was completed. Scale bar 5 100 µm.
In the course of this study, fifty-three fetal amniotic
sacs were injected with DiI and forty-one of the exposed
fetuses remained viable for subsequent analysis. The
injected fetuses were examined on days 9, 10, and 11 of
gestation to determine the distribution of DiI labeled
epithelial cells in the developing mandibular process.
DiI labeled only the cells on the surface of the fetus
that were in contact with the amniotic fluid. At E9, the
DiI was incorporated only in the membranes of the
epithelial cells covering the developing craniofacial
prominences (Fig. 6A). There was no labeling of cells in
the mesenchyme underlying the epithelium. Following
the contact of the two opposing mandibular prominences there was a DiI-labeled bilayered epithelial
seam along the line of fusion (Fig. 6B). There were no
labeled cells in the underlying mesenchyme. The
progress of fusion of the opposing mandibular prominences was associated with migration of the epithelial
cells to the surfaces of the mandible and the lack of any
migration of DiI labeled cells into the underlying
mesenchyme (Fig. 6C). The migration of midline epithelial cells to the surface region was evident by the
intense DiI-labeled epithelial triangle at those locations. The complete fusion of the mandible was associated with a mesenchyme without DiI-labeling in juxtaposition to a DiI-labeled surface epithelium. No
epithelial cells originally labeled with DiI transdifferentiated to a mesenchymal phenotype (Fig. 6D). With
regard to the DiI fluorescence intensity, variation in
intensity is a reflection of cell shape and membrane
surface area. In the midline, the epithelial cells are
columnar with a large membrane surface area and,
consequently, do not have a strong fluorescence, since
the DiI is distributed throughout the membrane. On
the other hand, at the adjacent surface epithelium,
some squamous epithelial cells are present, which
concentrate the DiI signal and increase fluorescent
intensity.
530
CHAI ET AL.
Fig. 4. Higher magnification of midline epithelia at the fusion site
during different stages of mouse embryo morphogenesis. A: The united
midline epithelia is 3 to 4 cell layers thick (me) at E10. B,C: Interruption of
extracellular matrix occurred as the fusion process was initiated (arrow).
D: On adjacent sections from the same mandibular prominence, complete
separation of oral (oe) and suboral epithelium (soe) was evident (arrow).
Scale bar 5 20 µm.
531
FUSION OF MANDIBULAR PROMINENCES
Fig. 5. There was no significant increase in lysosome activity at the
mandibular prominences fusion site. A,B: The midline seam was interrupted by mesenchymal cells and the epithelial triangle (arrow) and
contacting midline epithelium (double arrow) showed a slight increased
lysosomal activity. C,D: On completion of mandibular fusion at E11,
lysosomal staining was present in only a limited area of oral surface
epithelium (oe). There was no lysosomal activity observed in the mesenchymal cells adjacent to the midline during the mandibular fusion. Scale
bar 5 50 µm.
TGF-b3 Knock-Out Mice Have Normal Fusion of
the Mandible
the fusion site (data not shown). The TGF-b3 knock-out
phenotype resulted in cleft of secondary palate but had
no apparent effect on mandibular fusion.
The absence of TGF-b3 has been shown to inhibit
secondary palatal fusion; all pups homozygous for
TGF-b3 null mutants presented a cleft of the secondary
palate phenotype (Fig. 7C, arrow). Significantly, mandibular midline clefts were never observed in the
TGF-b3 (2/2) mutants (Fig. 7B). Histologic analysis of
serial-sections comparing wild type with homozygous
TGF-b3 (2/2) embryos did not show any difference at
DISCUSSION
The present study reports evidence that supports the
hypothesis that mandibular prominence fusion does
not require either apoptosis or epithelial-mesenchymal
transformation. The developmental process of mandibular prominence fusion starts at E9.5 (21–29 somites)
532
CHAI ET AL.
Fig. 6. There was no transdifferentiation of midline epithelial cells into
mesenchymal cells in the mandibular prominence. A: At E9, the DiI was
incorporated only in the membranes of the epithelial cells covering the
developing craniofacial prominences (arrows). There was no labeling of
cells in the mesenchyme (mes) underlying the epithelium. B: Following
the contact of the two opposing mandibular prominences there was a
DiI-labeled epithelial seams along in the midline (arrow). There were no
labeled cells in the underlying mesenchyme. B is at E9.5, which is
equivalent to Figure 2B. C: There was migration of the epithelial cells to
the oral (oe) and suboral (soe) epithelium and the lack of any migration of
DiI labeled cells into the underlying mesenchyme. C and Figure 2D are at
E10.5. D: The complete fusion of the mandible was associated with a
mesenchyme without DiI-labeling in juxtaposition to a DiI-labeled surface
epithelium. Scale bar 5 50 µm.
and is completed within 36 hr. The in utero labeling of
the mandibular prominences before fusion, and subsequent medial epithelial cell lineage analysis in vivo,
provided the possibility for the examination of mandibular fusion. During this process, midline epithelial cells
migrate to the oral surface of the fusing mandibular
arch. This positional reassignment for midline epithelial cells is in striking contrast to the fate of MEE
associated with secondary palate fusion. During palatal
fusion, the basement membrane underlying the MEE
cells is degraded and the epithelial cells migrated into
the mesenchyme and transdifferentiated into a mesenchymal phenotype (Fitchett and Hay, 1989; Griffith and
Hay, 1992; Shuler et al., 1991, 1992).
Two different observations on the fate of the palatal
MEE cells have been made that are particularly impor-
tant, in vitro. One observation reported epithelialmesenchymal transdifferentiation (Ferguson, 1988;
Fitchett and Hay, 1989; Shuler et al., 1991; Griffith and
Hay, 1992). The other observation showed that the
MEE cells migrate to adjacent epithelia (Carette and
Ferguson, 1992). These results have led to the suggestion that the MEE cells along a fusion line have two
possible fates: (1) epithelial-mesenchymal transformation, and (2) epithelial cells proximal to the oral surface
migrate to the surface position and retain their epithelial phenotype (Shuler, 1995).
During mandibular prominence fusion, the present
investigation was unable to identify evidence for an
epithelial-mesenchymal transformation fate for the midline epithelium covering the two opposing mandibular
prominences. Rather, the DiI-labeled cells appeared to
FUSION OF MANDIBULAR PROMINENCES
533
Fig. 7. TGF-b3 knock-out mice had normal fusion of the mandible. A:
Frontal view of normal wild type new born mouse. B: Frontal view of
TGF-b3 (2/2) mutant newborn mouse. There was no midline cleft in the
mandible. C: Transverse section of newborn mice with normal wild type at
the left and TGF-b3 (2/2) mutant (with arrow) on the right. All pups
homozygous for TGF-b3 null mutants presented a cleft of the secondary
palate phenotype (arrow). Scale bars 5 1 mm.
be incorporated to a new position assignment within
the oral surface. In comparing these results to those
previously observed during palatogenesis in vivo, it
would appear that the midline epithelial cells migrated
to adjacent epithelial rather than undergoing phenotypic transformation. The size of the fusion area and
the distance to the oral surface epithelium may be
critical features of whether midline epithelial cells
undergo either epithelial-mesenchymal transformation
or migration to the oral surface position. The relatively
small size of the fusion zone in the mandible may
permit all of the midline epithelial cells to retain their
phenotype and migrate to the surface.
Another explanation that might account for the disappearance of MEE cells at the fusion site of secondary
palate has been based on the possibility of programmed
cell death. This fate has been supported by two lines of
evidence. One data set indicates the appearance of
intracellular ultrastructural change consistent with
apoptosis. The second line of evidence in support of
programmed cell death is an increase of lysosome
activity at the fusion site during secondary palatal
fusion (Mato et al., 1966). Recent studies, however,
have shown that the slight increases in lysosomal
activity might be the result of increased intracellular
and extracellular remodeling by degradative enzymes,
rather than programmed cell death (Carette and Ferguson, 1992). In contrast, the epithelia at the midline of
the fusing mandibular prominences do not have increased lysosome activity and do not have intracellular
changes consistent with apoptosis. During mandibular
fusion, programmed cell death does not appear to play a
role in the fate of the midline epithelia.
Another potentially significant aspect of craniofacial
morphogenesis is the suggested function of autocrine
and/or paracrine controls by the growth factors and
their cognate receptors for midline epithelium during
either secondary palatal or mandibular prominence
fusions. For example, TGF-b3 is identified and specifically expressed in MEE cells of pre-fusion palatal
shelves and expression ceases shortly after the midline
epithelial seam is formed (Fitzpatrick et al., 1990;
Pelton et al., 1990). In vitro studies of depletion of
TGF-b3 gene product by using either antisense oligodeoxynucleotides or neutralizing antibodies prevented
secondary palatal fusion (Brunet et al., 1995). TGF-b3
534
CHAI ET AL.
null mutant mice have both delayed pulmonary development and cleft palate (Kaartinen et al., 1995). These
studies indicate an essential function of TGF-b3 ligand
in signal transduction processed during secondary palate fusion. TGF-b3 is also identified and specifically
localized during the formation of Meckel’s cartilage
within mandibular development (Chai et al., 1994).
However, the depletion of TGF-b3 using antisense
oligodeoxynucleotides did not result in the clefting of
Meckel’s cartilage, but rather reduced the anteriorposterior dimension of Meckel’s cartilage. In TGF-b3
(2/2) mutant mice, the mandibular prominence fusion
was normal and no sign of cleft mandible was noted.
Thus, the TGF-b3 mediated molecular mechanisms,
which govern the behavior of palatal MEE cells and
mandibular midline epithelial cells, would appear to be
quite different.
Craniofacial morphogenesis appears to have two
different developmental processes for the fate of midline epithelial cells in the zones of fusion. In the case of
relatively small fusion zones, as seen in mandibular
prominence fusion, the epithelial cells retain their
phenotype and become incorporated within the oral
epithelia covering the mandible. When the fusion zone
is larger, the epithelial cells closest to the surface may
migrate to and merge with the surface epithelia. Epithelial cells which have lost contact with the surface, due
to basement membrane degradation, become entrapped
in the midline of the secondary palate and undergo
epithelial-mesenchymal transformation. In the process
of fusion, a very small number of epithelial cells may
die; however, that does not provide evidence for programmed cell death. The presence of two alternative
fates for the midline epithelial cells further suggests
that the action of teratogens may be associated with
differential effects on these two complementary yet
different developmental processes. Cell lineage analyses can permit the cells to be identified and analyzed at
subsequent stages of development to determine the
molecular controls for these two processes.
5 µm intervals and stained with hematoxylin and eosin
for morphological evaluation.
EXPERIMENTAL PROCEDURES
Mouse Embryos
DiI-Labeled Cell Localization Techniques
Swiss-Webster mice were obtained from Simonsen
Labs (Gilroy, CA) and mated for 2 hr and the presence of
a vaginal plug established day 0 and hour 0. Mouse
embryos were dissected on either gestational days 9,
10, or 11 (E9, E10, and E11) to obtain the mandibular
prominences during the midline fusion process. External developmental staging of the mouse embryos was
evaluated according to Theiler (1989). The dissection
methodology was previously described (Slavkin et al.,
1989; Shum et al., 1993).
Histology
The mandibular prominences were fixed in 10%
buffered formalin, dehydrated in a graded series of
alcohols, cleared in xylene, and embedded in paraffin.
Each mandibular prominence was serially sectioned at
Scanning Electron Microscopy
Isolated mandibles were fixed in 2.5% glutaraldehyde (Pelco, Inc., Tustin, CA) in 0.1M sodium cacodylate buffer, pH 7.2, at 4°C for 2 hr. Specimens were
rinsed in buffer and post-fixed in 2% osmium tetroxide
(Pelco, Inc.) in 0.1M cacodylate buffer for 1 hr at 4°C,
dehydrated in graded alcohols and placed in perforated
Beem capsules in acetone. Specimens were then dried
in a critical-point drying bomb (Sorvall, Newtown, CT)
using carbon dioxide and mounted in specimen studs,
sputter coated with gold-palladium alloy in an argon
atmosphere (Hummer V, Technics); pulsed for 7 min at
9 V and 10 mA. The specimens were viewed with a
Cambridge S4-10 scanning electron microscope operating at 10 kV.
DiI Labeling Methods
Eight timed-pregnant Swiss-Webster mice were used.
The amniotic sacs were injected with DiI at gestational
age 8 days 22 hours. General anesthesia was induced
with an intraperitoneal injection of sodium pentabarbitol (50 mg/kg). The pregnant bicornuate uteri were
carefully exposed through a midline labarotomy and
the amniotic sacs counted. Sterile glass micropipets
were used for all injections. DiI working solution (0.025%
in normal saline, 1% ethanol) was made immediately
before injection from a 1003 DiI stock in 100% ethanol.
Each amniotic sac was transilluminated to identify the
fetus’s exact position in utero, and 10 µl of the DiI
working solution was microinjected through the wall of
the uterus into the amniotic fluid. The uterus was
returned to the abdominal cavity, the wound irrigated
and closed. The mice were subsequently sacrificed at
selected stages of fetal development associated with the
fusion of the mandibular processes of the first branchial
arch. The fetuses were dissected and the heads quick
frozen on dry ice for use in cryostat sectioning.
Frozen sections, 8 µm thick, were prepared from the
mouse embryonic heads with the sections made in a
coronal plane. The sections were mounted on glass
slides and immediately observed for DiI fluorescence
with a Zeiss (Thornwood, NY) fluorescent microscope at
an excitation wavelength of 546 nm and an emission
wavelength of 563 nm. The DiI fluorescence localization
patterns were recorded photographically on Ektachrome 400 film.
Immunocytochemistry
Specimens for light microscopy were fixed in Carnoy’s
fixative overnight at 4°C, dehydrated in a graded series
of ethyl alcohol, cleared in xylene, and embedded in
paraffin. Sections were cut at 5 µm in the transverse
plane. In preparation for immunohistochemistry, slides
were cleared in xylene and hydrated to water through a
FUSION OF MANDIBULAR PROMINENCES
graded series of alcohols. A monoclonal antibody (1D4B)
obtained from the Developmental Studies Hybridoma
Bank (Johns Hopkins University, Baltimore) was used
to detect regions of lysosomal activity during mandibular prominence fusion. Slides were then treated using
the Histostain-Streptavidin Peroxidase kit (for mouse
primary antibody) following the protocol provided by
the vendor (Zymed Laboratories, Irvine, CA).
Mice Deficient for TGF-b3
Mice lacking TGF-b3 were obtained by successful
disruption of the TGF-b3 locus on exon 6, which encodes mature TGF-b3 (Kaartinen et al., 1995). RT-PCR
analysis confirmed the absence of TGF-b3 transcripts
in null mutants. Morphological analysis was done to
compare the fusion of mandibular prominences between the wild type and homozygous knock-out of
TGF-b3 (2/2) mice.
ACKNOWLEDGMENTS
The monoclonal antibody (1D4B) developed by J.
Thomas August was obtained from the Developmental
Studies Hybridoma Bank maintained by the Department of Pharmacology and Molecular Sciences, Johns
Hopkins University School of Medicine, Baltimore, MD
21205, and the Department of Biological Sciences,
University of Iowa, Iowa City, IA 52242, under contract
N01-HD-2-3144 from the NICHD. This research was
supported by NIDR Center grant DE-09165.
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