/. Embryo/, exp. Morph. Vol. 38, pp. 217-226, 1977
Printed in Great Britain
217
Quantitative aspects of proliferation in the nasal
epithelium of the rhesus monkey embryo
By DORIS B. WILSON 1 AND ANDREW G. HENDRICKX 2
From the Division of Anatomy, Department of Surgery,
University of California, San Diego, and the Primate Research Center,
University of California, Davis
SUMMARY
Proliferation was studied in the nasal epithelium of rhesus monkey embryos ranging in
age from 26 through 41 days of gestation (stages 13-20). Labeling indices were tabulated 1 h
after an intrachorionic injection with [3H]thymidine, and the distribution of labeled cells
was determined at intervals ranging from 1 h to 11 h after injection. The labeling index
showed a chronological decrease from 69-4 % in the nasal placode at stage 13 to 31-6 % in
the nasal pit at stage 20. The vomeronasal epithelium was distinctive in that the basal cells
lost their ability to incorporate [3H]thymidine as early as stage 18. In the remainder of the
nasal epithelium, mitotic figures were initially confined to apical regions but later occurred in
basal regions as the embryonic pattern of proliferation became converted to the adult type.
INTRODUCTION
Development of the olfactory organ has been the subject of several studies on
the amphibian (Coghill, 1916), chick (Wesolowski, 1970), and rodent (Smith &
Monie, 1969; Smart, 1971; Vidic, 1971a; Breiphol, 1972; Breiphol, Mestres &
Meller, 1973; Waterman & Meller, 1973; Cuschieri & Bannister, 1975 a, b). The
olfactory organ and its innervation have also been described or briefly mentioned in studies on primate embryos (Schaeffer, 1910; Peter, 1913; Pearson,
1941 a, b; Streeter, 1942, 1945, 1948, 1951; Gilbert & Heuser, 1954; Warbrick,
1960; O'Rahilly, 1965,1967; O'Rahilly & Boyden, 1973; Andersen & Matthiessen, 1967; Vidic, 19716; Hendrickx et al, 1971).
Although it is generally accepted that the olfactory placodes and pits play a
significant role early in the development and growth of the facial region
(Waterman & Meller, 1973; DeMyer, 1975; Enlow & Azuma, 1975) and that
proliferation is an important event during these early developmental stages
(Andersen & Matthiessen, 1967; Smart, 1971), little is known about the developmental mechanisms concerned with these events, especially in primates. The
1
Author's address: Division of Anatomy, M-004, University of California, San Diego, La
Jolla, California 92093, U.S.A.
2
Author's address: Primate Research Center, University of California, Davis, California
95616, U.S.A.
218
D. B. WILSON AND A. G. HENDRICKX
present study was thus undertaken to obtain quantitative data on the proliferative process during early embryonic stages of the nasal epithelium in the
nonhuman primate.
The technique of tritiated thymidine autoradiography has been of considerable use in studying proliferation, particularly in the embryonic and neonatal
nervous system (Sidman, Miale, & Feder, 1959; Fujita, 1964; Martin & Langman, 1965; Langman, Guerrant & Freeman, 1966, Langman, 1968; Kauffman,
1968; Wilson, 1974; Wilson & Center, 1974). Although the technique is somewhat more difficult to use in the pregnant monkey, we have succeeded in labeling
early rhesus monkey embryos for varying periods of time by means of an intrachorionic method (Sawyer, Wilson, Anderson & Hendrickx, 1974). A series of
these embryos ranging in age from 26 through 41 days of gestation (stages
13-20) served as the basis for analyzing the process of proliferation during the
early developmental stages of the nasal epithelium and pits.
MATERIALS AND METHODS
Eighteen pregnant rhesus monkeys (Macaca mulatto) were injected with a
single dose of 100 /id [3H]thymidine (specific activity 6-7 Ci/mM) by the intrachorionic route involving exposure of the uterus by midline incision and
determination of the implantation site on the basis of myometrial vascularity
(Hendrickx et al. 1971). At periods ranging from 1 h to 11 h after injection, the
embryos were removed by hysterotomy and fixed in Carnoy's or in Serra's
fluid. The embryos were serially sectioned at 5 jum, prestained with eosin or the
periodic acid-Schiff method, and coated with Kodak NTB-2 emulsion (dilution
1:1) according to standard autoradiographic techniques (Kopriwa & LeBlond,
1962). The slides were stored at 4 °C or - 7 0 °C for 1-2 weeks, developed in
D-19, poststained with hematoxylin, and mounted. The embryos were staged
on the basis of criteria used for monkey embryos (Hendrickx et al. 1971;
Hendrickx & Sawyer, 1975) and for human embryos (Streeter, 1942, 1945,
1948, 1951). At least two embryos were obtained for each stage of development.
Labeling indices were determined for each embryo by calculating the number
of labeled nuclei/total nuclei in every fourth section through the two olfactory
anlagen. Nuclei with four or more grains were considered labeled. Approximately 1000 nuclei were tabulated for each embryo.
RESULTS
Stages 13, 14. At stage 13 each nasal placode consisted of an epidermal
thickening of tall columnar cells on the ventrolateral surface of the head (Fig. 1).
The placode was widely separated from the telencephalon by a mass of
mesenchyme cells, many of which were labeled with [3H]thymidine. The central
region of the placode was the thickest; peripherally the placode cells tapered and
Proliferation in monkey nasal epithelium
Fig. 1. Nasal placode at stage 13 1 h after injection of [3H]thymidine. x 200.
Fig. 2. Nasal placode at stage 13 9 h after injection of [3H]thymidine. Arrows
indicate labeled mitotic figures, x 250.
Fig. 3. Invagination of nasal placode at stage 14 to form the nasal groove 4 h after
injection of [3H]thymidine. x 330.
Fig. 4. Nasal pit at stage 15 11 h after injection of [3H]thymidine. Mesenchyme cells
in the medial nasal process (MNP) and lateral nasal process (LNP) are well labeled.
xlOO.
219
220
D. B. WILSON AND A. G. HENDRICKX
merged with adjacent epidermal cells. One hour after injection the basal portions
of the placode contained oval nuclei labeled with [3H]thymidine, whereas unlabeled mitotic figures occurred in the apical portions. No regional differences
could be detected with respect to the percentage of labeled cells, and the mean
labeling index for the entire placode 1 h after injection was 69-4 %. By 9 h after
injection, almost all of the nuclei near the surface were labeled, including those
in mitosis (Fig. 2).
During stage 14 the placode began to invaginate and form a nasal pit, which
was widely separated from its counterpart on the other side. The placode
epithelium was approximately 8-10 nuclei deep at its thickest part. One hour
after injection of [3H]thymidine the labeling index was 61-7 %, with the labeled
nuclei concentrated in the basal half of the epithelium. Four hours after injection
the labeled nuclei had begun to migrate toward the surface of the epithelium,
but there were relatively few labeled mitotic figures (Fig. 3).
Stages 15, 16. During stage 15 the nasal pit had further invaginated and consisted of a shallow groove flanked medially and laterally by the medial and
lateral nasal processes, respectively. One hour after injection, labeled nuclei
were randomly distributed in the basal layers of the nasal pit epithelium, and
the labeling index was 45-8 %. The mesenchyme of the nasal processes was also
heavily labeled. By 11 h after injection the labeled nuclei in the nasal pit epithelium had shifted from the basal region toward the surface, and virtually all
of the mitotic nuclei were labeled (Fig. 4).
At stage 16 the medial and lateral nasal processes had grown ventrally, and the
ventral region of the nasal pit became fused together to form the nasal fin, the
epithelium of which was continuous dorsally with the nasal pit and ventrally
with the roof of the oral cavity (Fig. 5). Labeled nuclei were present in the nasal
fin epithelium. With the formation of the nasal fins, the two nasal pits showed a
slight convergence toward one another and thus became more ventrally situated.
The medial wall of each nasal pit also showed a slight medial bulge representing
the vomeronasal organ. The epithelium of the nasal pit was still relatively well
labeled, although the labeling index 1 h after injection had dropped to 37-3 %.
At this stage a few mitotic figures could be detected in basal regions of the
FIGURES 5-7
Fig. 5. Nasal pit at stage 16 1 h after injection of [3H]thymidine. Arrow indicates
nasal fin representing a fusion of epithelium at the floor of the nasal pit. The vomeronasal organ (VN) is represented by a bulge along the medial wall of the nasal pit.
xl20.
Fig. 6. Nasal pit at stage 18 1 h after injection of [3H]thymidine. The vomeronasal
organ shows an intermediate zone of labeled nuclei (small arrows). Large arrow
indicates band of nerve fibers extending from vomeronasal organ, toward brain.
xl75.
Fig. 7. Vomeronasal organ at stage 20 1 h after injection of [3H]thymidine. Arrows
indicate basal layers of rounded unlabeled nuclei, x 300.
Proliferation in monkey nasal epithelium
221
EMB 38
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D. B. WILSON AND A. G. HENDRICKX
epithelium, in addition to numerous mitotic figures in the apical regions. As in
previous stages, the mesenchymal cells in the medial and lateral nasal processes
showed an abundance of labeled nuclei.
Stages 17-20. At stage 17 the epithelium of the nasal fin began to disappear,
and the nasal septum became apparent as a well labeled mesenchymal condensation in the midline. By stage 18 the nasal pits further converged medially
toward one another. Regional differences in labeling could not be detected
between the medial, lateral, or dorsal walls of the pits, and the labeling index was
34-5 %. Although the vomeronasal organ contained labeled nuclei, these were
located in an intermediate zone between the basal and superficial regions of
the epithelium (Fig. 6). A narrow band of unlabeled cells occurred basally, and
nerve fibers could be seen extending from this region of the organ dorsally and
medially toward the brain. By stage 20 the labeling index of the nasal epithelium
was 31-6%. However, the thickened wall of the vomeronasal organ showed
relatively few labeled nuclei and several distinct layers of rounded unlabeled
nuclei in the basal region of the epithelium (Fig. 7).
DISCUSSION
In the adult olfactory epithelium the olfactory receptor neurons and supporting cells are believed to be constantly generated by basal cells, in contrast to the
usual situation in the adult nervous system where neurons are not renewed
(Moulton, Celebi & Fink, 1970; Graziadei, 1971, 1975a, b). However, during
the early stages of embryonic development the nasal epithelium initially exhibits
the same type of proliferative activity as do neuroepithelial cells in the spinal
cord and brain, i.e. DNA-synthetic nuclei are located basally, and the nuclei
subsequently migrate apically to undergo mitosis (Smart, 1971; Cuschieri &
Bannister, 1975 a). This pattern of proliferation changes in later embryonic
stages when mitotic figures begin to occur in the basal regions of the epithelium.
Eventually the mitotic activity becomes predominant in the basal layers. This
conversion from an embryonic neural type of proliferation to an adult stratified
epithelial type was noted in the mouse of 12 days' gestation, at which time
mitotic figures could be detected in basal regions of the nasal epithelium (Smart,
1971; Cuschieri & Bannister, 1975a). In the rhesus monkey embryos of the
current study, a similar conversion was noted at stage 16, which is roughly
comparable to 11^ days' gestation in the mouse (Theiler, 1972).
In our early rhesus monkey embryos the basal region of the epithelium was
extensively labeled 1 h after injection of [3H]thymidine, but a relatively long
period of time elapsed before labeled mitotic figures could be detected apically.
This suggests that the length of the cell cycle of nasal epithelial cells in the
primate embryo may be considerably longer than that previously observed for
embryonic neuroepithelial cells in the central nervous system (Kauffman, 1968;
Wilson, 1974; Wilson & Center, 1974). However, additional quantitative studies
Proliferation in monkey nasal epithelium
on the length of the cell cycle in primate embryos are necessary before adequate
comparisons can be made with the cycle in other mammalian embryos.
The labeling index gradually decreased from a high point of 69-4 % in the
rhesus monkey nasal placode at stage 13 to 31-6 % in the nasal pit at stage 20. A
similar chronological decrease also was noted in our previous studies on the
epithelium of the otic and lens placodes in rhesus monkey embryos (Wilson,
Sawyer & Hendrickx, 1975; Wilson, Hendrickx & Sawyer, 1976). However, the
decrease in the nasal epithelium was much more gradual than that in the lens
placode where the labeling index fell markedly during the early invagination
stages. The nasal epithelium also differed from the lens and otic placodes in its
apparent lack of spatial gradients of incorporation. In the otic vesicle the dorsal
region showed a decrease in labeling index much earlier than in ventral regions,
and the endolymphatic duct very early lost its ability to incorporate [3H]thymidine (Wilson et al. 1975). In the lens the deep wall of the lens vesicle failed to
incorporate label even before the lens lost its contact with the surface epidermal
cells (Wilson et al. 1976).
Several other differences exist between the nasal rudiments and the lens and
otic rudiments. Of the three, the nasal pit is the only one to retain its contact
with surface epidermal cells, whereas the lens and otic pits pinch off completely
to form vesicles. Also, in contrast to the lens and otic placodes, the nasal placode
is not in close contact with the neurectoderm of the neural tube. The significance
of these differences remains to be determined, although it is possible that one or
more of these features may be causally related to the eventual conversion of the
embryonic pattern of proliferation to the adult type whereby the new cells are
continuously generated from a basally located population of precursors.
In the rhesus monkey embryo the vomeronasal organ was well developed and
similar to that described in the human (Streeter, 1948, 1951; O'Rahilly, 1967),
in contrast to the baboon embryo where the vomeronasal organ was quite
rudimentary in appearance (Hendrickx et al. 1971). In the rhesus monkey
embryo the vomeronasal organ was identifiable as early as stage 16 and consisted of a thickened area on the medial aspect of the nasal pit. By stage 18 the
pattern of labeling in the vomeronasal organ differed from that in the rest of the
nasal epithelium. The labeled cells were confined to an intermediate zone,
whereas the basal cells had become rounded and had lost their ability to incorporate tritiated thymidine. This loss corresponded with the appearance of nerve
fibers extending from the organ toward the brain. Early embryonic differences
in the primate vomeronasal organ have also been demonstrated histochemically
(Andersen & Matthiessen, 1967).
There has been some question as to whether the epithelium of the nasal
placode and pit actively invaginates during the early stages of development, or
whether the deepening of the nasal groove results from proliferation in the
medial and lateral nasal processes, thereby passively pushing the epithelium
upward, or whether both factors are involved (Schaeffer, 1910; Warbrick, 1960).
15-2
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D. B. WILSON AND A. G. HENDRICKX
The nasal epithelium is obviously extremely active in generating new cells during
these early stages. Indeed, the labeling index of the epithelium in the early nasal
pit was 69-4 %, which is higher than that observed at comparable stages in other
sensory placodes of the monkey (Wilson et al. 1975; Wilson et al. 1976). This
mitotic activity resulted not only in a thickening of the nasal epithelium but also
in an elongation of the nasal pits. However, the mesenchyme of the medial and
lateral nasal processes was also heavily labeled, and it would appear that their
rapid growth played an important role in delimiting the nasal pits ventrally, thus
ultimately forming the floor of each pit as the nasal fin formed by fusion of the
epithelia from the two nasal processes.
Some studies have emphasized the presence of degenerating cells in the nasal
fin (Hies, 1970; Vermey-Keers, 1972), whereas others describe large numbers of
mitotic figures (Andersen & Matthiessen, 1967). In our rhesus monkey embryos
the nasal fin contained labeled nuclei, as well as degenerating cells. It is possible
that portions of the epithelium may disintegrate and thereby allow mesenchymal
cells to invade the area ventral to the nasal pits, while other regions of the
epithelium are generating new cells to contribute to the floor of the nasal pits
and the roof of the oral cavity. However, these possibilities warrant further
investigation, since epithelial proliferation, fusion, and disintegration are important developmental events in numerous other embryonic organs as well as in
the nasal and palatal regions of the face.
This work was supported by National Institutes of Health Grants 1P01 HD08658-03 from
NICHD, DE03927 from NIDR, and RR00169. The authors wish to express appreciation to
Dr John Anderson for performing the animal surgery and Kathryn Jereb for the histological
preparations.
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3
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{Received 16 August 1976)