Development of the optic nerve of the rat - Investigative ...

Development of the optic nerve of the rat 

Toichiro Kuwabara 

Development of the rat optic nerve is studied electron microscopically. By marked bionecrosis, 

many neuroepithelial cells of the fissure portion of the optic stalk are eliminated immediately 

following optic cup formation. A small number of the surviving neuroepithelial cells forms, 

the tubular optic stalk. The wall cells of the stalk elongate and proliferate to become a cluster 

of cells at the retrobulbar region. These cells differentiate into glia cells, astrocytes first and 

oligodendroglia cells second. Axons invade into the intercellular spaces of the elongating stalk 

cells which are differentiating into astrocytes. The invading axons are found first in the space 

at the basal portion of the stalk cells, or the peripheral zone of the optic nerve. Myelination 

occurs in the later stage of development. The fine processes of the oligodendroglia cells which 

surround groups of axons, eliminate the cytoplasm, and become the first 7nyelin membrane. 

Key words: optic nerve, development of optic nerve, axon, glia cell, myelination, rat. 

A lthough the fine structure of the optic 

nerve has been described by several authors. 

1 " 1 " the cytologic details of developmental 

differentiation of this tissue have 

not been well documented; only a few 

observations on the myelin formation 

which occurs in relatively later stages have 

been reported in recent literature. 1115 The 

present study deals with electron micro- 

From the Laboratory of Vision Research, National 

Eye Institute, National Institutes of Health, 

United States Department of Health, Education, 

and Welfare, Bethesda, Md., and Howe 

Laboratory of Ophthalmology, Harvard University 

Medical School, Boston, Mass. 

Initial part of this investigation was supported by 

Research Grant EY 00006 from the National 

Eye Institute at Howe Laboratory of Ophthalmology, 

Harvard Medical School. 

Submitted for publication Dec. 26, 1974. 

Reprint requests: Dr. Toichiro Kuwabara, National 

Eye Institute, Building 6, Room 213, National 

Institutes of Health, Bethesda, Md. 20014. 

732 

scopic observations of the differentiation 

of each cell component of the developing 

rat optic nerve, which occurs during the 

period immediately following the optic 

cup formation to two postnatal weeks old. 

Material and methods 

Fetuses and postnatally developing albino rats 

of the Charles River CD strain were used in this 

study. Fetuses between the thirteenth day and 

birth were obtained by killing pregnant rats of 

specific gestation dates. Developing young rats 

were killed on the postnatal first through seventh, 

fourteenth, and twenty-first days. At least three 

different animals were studied at each developing 

stage. 

The whole head or the posterior half of the 

globe, depending on the size of the animal, containing 

the optic nerve and surrounding tissue, 

was excised and fixed in 4 per cent glutaraldehyde 

in 0.15 M phosphate buffer solution (pH 7.2) for 

20 minutes at room temperature. During the 

initial fixation, the tissue to be studied was carefully 

dissected out and trimmed into small pieces 

measuring not more than 0.3 mm. 3 The whole 

optic stalk including the posterior eye and the

Volume 14 

Number 10 

Rat optic nerve 733 

brain tissue was processed as one piece in early 

fetuses, and the optic nerves of animals older 

than the eighteenth embryonal day were divided 

into three pieces: postbulbar, central (midcanalicular), 

and chiasma portions. The tissue 

was postfixed in 1 per cent osmium tetroxide in 

the same buffer solution for 90 minutes at 4° C. 

After further trimming and orientation under a 

dissecting microscope, the small pieces were dehydrated 

in a series of ethyl alcohol, treated with 

propylene oxide, and embedded in an epoxy resin 

following Luft's method. 1 " 

Sections (0.5 to 1.0 y. thick) were stained with 

alkaline toluidine blue for light microscopic study. 

Ultrathin sections were stained with uranyl acetate 

and lead citrate and were examined by an electron 

microscope with an accelerating voltage of 

80 KV. 

Results 

The optic stalk, measuring about 200 /± in 

length, becomes recognizable immediately 

following the formation of the optic cup 

on the thirteenth fetal day (Fig. 1). The 

invaginating fold of the inner layer of the 

cup extends posteriorly and becomes the 

fissure which disappears rapidly as development 

progresses. The whitish nerve 

tissue becomes grossly visible on about the 

sixteenth day. The most active differentiation 

of the optic nerve appears to take 

place between the sixteenth and eighteenth 

day. 

On the day of birth, the optic nerve is 

about 2 mm. long and the configuration 

of the chiasma is clearly formed. Myelination 

of the nerve fibers, however, begins 

on the postnatal fifth day and continues 

actively until the end of the second week. 

The developmental process appears to 

slow down considerably by the end of the 

third postnatal week and no appreciable 

alteration in the cytologic appearance is 

observed after this period. 

Optic stalk. The tubular optic stalk is 

formed at the isthmus of the neurovesicle 

between the outpouching ocular tissue and 

the central nervous system. The earliest 

optic stalk consists of a single layer of 

neuroepithelial cells. The invagination of 

the optic cup extends posteriorly into the 

lower portion of the stalk and becomes 

Fig. 1. Early optic stalk of a 14-day-old fetus. 

The inner layer of the optic cup is continuous to 

the invaginated portion of the fissure. Epoxy 

sections, toluidine blue. xl30. 

Fig. 2. Disc area of a 14-day-old fetus. Many 

necrotic cells are present in the inner layer of 

the optic cup (arrow). Epoxy section, toluidine 

blue. x260.

734 Kuioabara Investigative Ophthalmology 

October 1975 

•'. 

Fig. 3. Central portion of the stalk of a 15-day-old fetus. Original neuroepithelial space (*) 

is open. Cells are firmly attached to each other by apicolateral junctions (arrows). x7,000. 

Insert shows details of the junctional zone. The junctions consist of chains of desmosomes and 

gap junctions, The cytoplasm contains abundant polysonies. xl7,000. 

the fissure. A cross-section of the fissure 

zone of the optic stalk reveals a structure 

similar to that of the optic cup—a single 

outer cell layer and an invaginated layer 

a few cells thick. 

The cells of the outer layer remain unchanged 

for a few days, whereas a great 

number of the neuroepithelial cells of the 

indented portion of the fissure, especially 

of the thick layer directly next to the 

retina, become degenerative and disappear 

from the area during the first two 

to three days following the stalk formation 

(Fig. 2). The cells which have escaped 

the degeneration form a tube-like 

tissue of a single cell layer. These cells 

are firmly attached to each other at the 

apicolateral zone (Figs. 3 and 17). On 

the fourteenth day, cells of the optic stalk 

begin to elongate. Both the apical and the 

basal attachments of the elongating cells 

appear to remain intact and form large 

intercellular spaces at the basal portions. 

The original neuroepithelial lumen becomes 

almost nonexistent on the fourteenth 

day. Proliferation of the stalk cells 

with mitotic activity is observed at the 

apical zone until the sixteenth day. The 

proliferated cells which have no basal attachment 

form a large cluster at the 

retrobulbar area (Figs. 4 and 5). The 

cluster of cells tapers toward the posterior 

but again, a large cluster appears near the 

chiasm. On the fifteenth day, the stalk becomes 

an oval piece having a cluster of 

cells in the upper, off-center zone (Fig. 4).

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Fig. 4. Cross-section of the optic stalk of a 15.5-day-old fetus. Proliferating stalk cells form 

a cluster in the upper center. Axons have invaded into the peripheral zone of the stalk. Epoxy 

section, toluidine blue. *260. 

Fig. 5. Longitudinal section of the optic stalk of a 15.5-day-old fetus. Axons extend mainly 

into the lower periphery of the stalk ( *), A small number of axons are seen in the upper 

periphery also (arrow). The cluster of the stalk cell extends about 0.5 mm. behind the globe. 

Epoxy section, toluidine blue. *180. 

Several elongating stalk cells maintain their 

basal attachments and become the marginal 

limit of the optic nerve. The original 

basement membrane of these cells is prominent 

beneath the cytoplasm. Axonal processes 

are found in the newly formed lateral 

intercellular spaces, first in the basal 

portion in the fissure zone and eventually 

all around the stalk (Fig. 5). 

The continuity between the pigment 

epithelium of the retina and the cells of 

the optic stalk is broken on the fourteenth 

day. The thick connective tissue separates 

the pigment epithelium from the optic 

stalk on the seventeenth day. The cluster 

of the elongated stalk cells proliferate 

rapidly at their apical portion and differentiate 

into glia cells. 

Axons. During the fourteenth to sixteenth 

day, cells in the inner layers of the 

retina and of the central nervous system 

show profound proliferation and differentiation. 

Also, the outer layer of the 

optic cup differentiates into the pigment

736 Kuwabara Investigative Ophthalmology 

October 1975 

Fig. 6. The inner portion of the developing retina of a 14-day-old fetus. Numerous axons are 

loosely packed in the intercellular spaces formed by Mijller's cell. ILM: Inner limiting membrane. 

x24,800. 

epithelium. The ganglion cell is found to 

be the first neural cell to differentiate in 

the retina. The cells which have separated 

from the basement membrane of the invaginated 

portion of the optic cup on 

around the twelfth to thirteenth day begin 

increase cytoplasmic volume at the inner 

side. The axon is extended from a small 

conical outpouching in which fine vesicles 

are packed. Details of this process have 

been reported previously. 17 The developmental 

process of the axon seems to be 

extremely rapid. On the fourteenth day, 

the inner layer of the retina is filled with 

newly formed axons (Fig. 6). Axons are 

uniformly small (average 0.2 to 0.3 /x in 

diameter) and consist of electron lucent 

cytoplasm in which a few wavy microtubules 

are present. Small mitochondria 

are also found occasionally. The extending 

tips of the axons contain clusters of small 

vesicles. 

The extending axons invade the lower 

portion of the optic stalk first (Fig. 5). 

Fine structurally, the axon bundles are 

found in the lateral spaces between the 

elongating stalk cells, especially at the 

basal portions, but not at all in the neurovesicular 

lumen nor in the fissure itself. 

Axons are small and are loosely packed 

and form groupings of various sizes apparently 

depending upon the availability 

of the intercellular spaces (Fig. 7), As the 

axons increase in size, the optic nerve becomes 

bigger as well as more compact. 

This developmental process is extremely 

rapid. The axon fibers become variable 

in size and are divided into small groups 

by the slender stalk cells which are differentiating 

into glia cells. Cross-section of the 

optic nerve of the sixteenth fetal day reveals 

that axon processes measuring around 

0.3 p. in diameter contain a few wavy 

microtubules, occasional mitochondria, and 

a small number of smooth endoplasmic 

reticulum (Fig. 8). The interaxonal spaces 

appear to be filled with a certain thin fluid 

but no cellular components are present. 

Axons are found most abundantly in the 

retrobulbar zone and in the chiasmal portion 

of the developing optic nerve. Also, 

the differentiation of glia cell components 

appears to be more advanced in these 

areas. In the optic nerves of two different

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Fig. 7. The peripheral portion of the optic stalk of a 15-day-old fetus. Elongating stalk cells 

form large intercellular spaces which are filled with small axons and glia processes. The cell 

in the center (*) is differentiating into an astrocyte. The cytoplasm contains microtubules 

and filaments. xl0,000. Insert shows wavy microtubules and vesicles in the tip of a growing 

axon. x25,200. 

15-day-old fetuses, there is a considerably 

slender portion in the central part of the 

nerve in which axon fibers are sparsely 

distributed. 

Glia cells. Glia cells appear to develop 

from the stalk wall cells. The differentiation 

process of the stalk cell has been described 

above (Figs. 2 through 4). 

On the fifteenth day, the optic nerve 

becomes oval in cross-section. A cluster of 

cells which are surrounded by axons is 

present in the upper off-central zone, especially 

of the retrobulbar segment. The 

cells in the cluster proliferate with a moderate 

mitotic activity for about two days. 

After the disappearance of the neuro-

738 Kuwabara Investigntive Ophthalmology 

October 1975 

Fig. 8. High magnification of the growing axons. A, lS-day-old fetus. The base of the stalk 

cells form the peripheral limit of the optic nerve. The arrow indicates the basement membrane. 

x32,000. B, 16-day-old fetus. Axons contain regularly spaced microtubules. x51,200. 

epitheliar lumen, the apical junctions of 

the stalk cells disappear. The proliferated 

cells begin to disperse into the extending 

axon bundles. The cytoplasm of these early 

glia cells contains abundant rough endoplasmic 

reticulum and a moderate number 

of mitochondria. Some original stalk cells 

which have elongated initially appear to 

move their nuclei to the basal portion. 

These cells contain relatively sparse membranous 

micro-organelles (Fig. 8). Also, 

cells with similar cytologic structure are 

present occasionally among the axons and 

other glia cells. 

The cells which proliferate in the earlier 

stage appear to become the astrocytes. 

The astrocytes begin to extend large 

branches into the axon bundles. The cytoplasm 

begins to contain numerous filaments, 

microtubules, and various microorganelles 

(Fig. 9). The extending process 

of the astrocytes often shows prominent 

junctions between them (Fig. 9, insert). 

At a slightly later stage, cells with darker 

cytoplasm begin to appear in the central 

zone of the cluster (Fig. 10). The cytoplasm 

of these cells contains abundant 

rough endoplasmic reticulum, free ribosomes, 

and microtubules. The cells disperse 

into the nerve tissue also, but their 

number is small until the second to third 

postnatal day. These cells appear to become 

oligodendroglia cells. At the time 

of birth, both glia cells are distributed diffusely 

throughout the nerve, but they are 

often arranged in strand-like fashion between 

the axon bundles (Fig. 11). Oligodendroglia 

cells appear to proliferate gradually 

with a moderate mitotic activity. Fine 

branches of the oligodendroglia cells appear 

to extend after the astrocytes have 

divided the axon bundles into groups. This 

occurs during the first week after birth. 

Despite the rich micro-organelles in the 

somar cytoplasm, the extending fine processes 

of the oligodendroglia cells con-

V ultima 14 

Number 10 


Fig. 9. A portion of astrocytes in a 16-day-old fetus. Axons are divided into groups. The 

cytoplasm of the astrocyte contains rough endoplasmic reticulum, microtubules, and filaments. 

x32,500. Insert shows junctions between the cell processes of the differentiating a-stroeytes, 

17-day-old fetus. x48,400. 

Fig. 10. Optic stalk of a 15-day-old fetus. A, hyperchromatic cells appear in the cluster of 

the stalk cell in the retrobulbar zone. Epoxy section, toludine blue. x480. 8, electron micrograph 

of the hyperchromatic cell. The cytoplasm contains abundant ribosomes. x 13,000.


October 197.5 

1 i s . iH . •: li* 

°i 3 

» 

^?r 

« 

13 * I 

Fig. 11. Optic nerves in the first postnatal week. A, 3-day-old rat. Glia cells form strand-like 

arrangement but they distribute throughout the nerve. Epoxy section, toluidine blue. x260. 

B, one-week-old rat. Clia cells are distributed diffusely. x480. 

Fig. 12. Cross-section of the nerve on the postnatal eighth day. Fine processes of oligodendroglia 

cells surround group of axons (*). The processes become double membranes in several locations 

(aiTows). x40,000.

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Fig. 13. Postnatal tenth day. A, serpentine double-cell membrane which, led by a small 

cytoplasm of the glia cell (°), extends over a few axons (arrows). x40,000. B> axons are 

surrounded by a relatively large glia cell element (*) and by the double membranes (double 

arrows). x58,400. 

tain sparse micro-organelles. They consist 

of the electron lucent cytoplasm and 

are distinguishable from those of the astrocyte 

which contain rich filaments. These 

thin processes appear to produce myelin 

sheaths at a later date, 

Myelination. Myelination of the optic 

nerve begins at a relatively later stage. 

During the first postnatal week, fine processes 

of the oligodendroglia cell begin to 

extend profoundly in the space between 

axons. On the eighth and ninth days, when 

the diameter of the optic nerve measures 

about 200 ju and the development of the 

retinal photoreceptor elements is considerably 

advanced, the first sign of myelination 

is noted in the area immediately behind 

the globe and in the chiasm. The 

extending thin-cell processes begin to surround 

groups of axons. These thin processes 

become a double-cell membrane 

structure, eliminating the cytoplasmic matrix 

in several locations (Fig. 12). These 

seem to be the earliest myelin membrane. 

The early myelin membrane seems to attach 

to a group of axons instead of an individual 

fiber. The tip portion of the process 

which becomes the mesoaxon seems to preserve 

a small amount of the cytoplasm 

(Figs. 12 and 13, A). Also, the usual myelination 

process in which a few axons are 

surrounded by a large cytoplasm of the glia 

cell is occasionally found (Fig. 13, B). 

During the next few days the number 

of double-membrane structures increases 

markedly. Many axons are surrounded 

completely by these membranes and by 

layers of lamellar membranes. By the end 

of the second week, almost all axons are 

found to be surrounded by myelin sheaths 

(Fig. 14). The nodes of Ranvier, the area 

where cytoplasms of two oligodendroglia 

cells meet, are frequently found in this 

stage (Fig. 15). By the end of the third 

week, all axons become myelinated. Fine 

processes of the astrocytes then begin to 

fill in the spaces between the myelinated 

nerve fibers.

742 Kuioabara Investigative Ophthalmology 

October 1975 

Fig. 14. Most axons are myelinated on the twelfth day. x8,000. 

O*e=»» 

Fig. 15. Early Ranvier's node in a 10-day-old rat. Two processes of the myelin-fomiing glia 

cells meet each other (arrow). x40 ; 000. 

Meninges and septa. The basal portions 

of the original neuroepithelial cells which 

have survived the early bionecrosis remain 

at the marginal zone of the stalk together 

with their basement membrane. 

These cells become tall and proliferate at 

their apical zone to differentiate into glia 

cells but they eventually become flat and 

form the outer limit of the optic nerve, the 

mantle glia. The cytoplasm of these cells is 

not distinguishable from that of the astrocyte. 

A thin connective tissue consisting of 

collagen fibers and a few fibroblasts is 

formed immediately outside of the basement 

membrane of the optic stalk on the 

fifteenth fetal day. This is the pia mater. 

The blood vessels around the optic nerve, 

the arachnoidal plexus, become significantly 

numerous during the first postnatal 

week. At about the same time, young 

mesenchymal cells begin to arrange in a 

circular pattern around the optic nerve 

and become the dura mater.

Volume 14 

Number 10 


Fig. 16. Development of the blood vessels in the optic nerve. A, 14-day-old fetus. Blood 

vessels are seen in the fissure. B, lG-day-old fetus. The fissure is closed but blood vessels are 

trapped within and are developing into large vessels. Both epoxy section, toluidine blue. x260. 

C, A blood capillary found in a newborn rat optic nerve. The capillary endothelium is thick-. 

The basement membrane is also thick, x 13,000. 

Invasion of blood vessels and connective 

tissue into the optic nerve begins postnatally. 

Thick basement membranes are 

always found along the invading vascular 

tissue. Although the septa is not conspicuous 

in the rat optic nerve, fibroblasts 

and collagen fibers are present regularly 

along the blood vessels of the adult tissue. 

At the time of optic stalk formation, numerous 

blood vessels are found in the loose 

mesenchymal tissue in and around the 

optic cup. The fissure is also filled with 

vascularized connective tissue. Some of 

these blood vessels seem to remain and 

develop into the large vessels of the retina 

and the optic nerve (Fig. 16). However, 

development of the optic nerve appears 

to take place without the aid of specific 

blood vessels. 

Discussion 

The developmental process of the rat 

optic nerve is summarized in the drawing 

(Fig. 17). The first step of the differentiation 

of the optic nerve apears to be elimination 

of excess cells by bionecrosis. Most 

of the neuroepithelial cells of the invaginated 

portion of the stalk fissure which 

are continuous to the developing retina 

degenerate and disappear immediately following 

the optic cup formation. Bionecrosis 

has been observed in the developing nervous 

tissue and its significance has been 

discussed. IS - l!1 Among several theories, production 

of inductive substances-" or energy 

sources for the development of the surrounding 

tissue'-' 1 has been believed to be 

the main purpose of the morphogenetic 

bionecrosis. The extensive degeneration of 

the developing optic nerve in the earliest 

stage, however, seems to be for elimination 

of unnecessary cells. The abundant 

neuroepithelial cells at the border zone 

between the optic stalk and the retina are 

apparently unnecessary in formation of the 

optic nerve. Only certain cells survive in


October 1975 

Fig. 17. Diagrammatic representation of the development 

of the optic nerve. Numbers indicate 

fetal days. See text for explanation. 

this area to become the optic stalk. 

After the elimination of many cells, the 

optic stalk becomes a tube consisting of a 

single cell layer wall. The stalk cells proliferate 

at their apical zone and fill up the 

tubular lumen rapidly. These cells appear 

to be designated to differentiate into glia 

cells. Astrocytes differentiate first from the 

proliferating wall cells. Development of 

the processes of the astrocyte appears to 

occur in two stages; the large processes 

divide the axons into large groups in the 

early stage, and finer processes extend to 

fill up the minute spaces between axons 

following the myelination. Oligodendroglia 

cells differentiate at a slightly later stage. 

Cells with darker cytoplasm become distinguishable 

in the cluster of the stalk cells. 

Both glia cells disperse rapidly throughout 

the optic nerve, but the oligodendroglia 

cells appear to proliferate in the later 

stage, mainly postnatally. Delayed maturation 

of the oligodendroglia cell has been 

demonstrated by Hirose and Bass. 22 Some 

small glia cells which have a cytoplasmic 

appearance similar to that of the third glial 

cell type 23 are found in the early developing 

optic nerve. However, its function was 

not demonstrated in this study. 

Although the cluster of the embryonal 

glia cells at the retrobulbar zone disappears 

during the differentiation of glia 

cells, it appears to be the origin of the 

highly cellular zone behind the lamina 

cribrosa of the adult optic nerve. This 

zone of the optic nerve may be serving as 

the germinal center of the glia cells 

throughout life. 

This study has demonstrated the exact 

location of the axonal invasion into the 

optic nerve at its early developmental 

stage. Axon bundles are seen first in the 

lateral intercellular spaces of the basal 

portion of the elongating stalk cells. Nerve 

fibers are not seen in the stalk lumen, fissure, 

or outside of the optic nerve. Bundles 

of the nerve fibers are divided into smaller 

groups by processes of the astrocytes 

which develop at an early stage. The presence 

of the relatively axon-free area halfway 

between the globe and the chiasm in 

15-day-old fetuses suggests that the axons 

extend into the optic nerve from two 

origins. These findings indicate that a large 

number of centrifugal fibers invade into 

the retina in the early stage of eye formation. 

However, it is not possible to trace 

a further extension of these fibers into 

the retina in the present observation. 

Myelination of the axons occurs at a 

rather late stage. Several axons are surrounded 

by fine processes of the glia cell 

as a group. The first myelin is apparently 

formed by the collapse of these glia cell 

processes. Although axons are occasionally 

found within a large cytoplasm of the glia 

cell, it is rare to find spiral myelination 

around the individual axons in the early 

stage. The thinned myelin membranes appear 

to extend between axons sinuously. 

This finding is somewhat different from 

that of the myelination of the peripheral 21 

and central nervous system. 25 This has not 

been described in the developing optic 

nerve by earlier investigators. However, 

the origin of these myelin-forming processes 

are the oligodendroglia cells, as 

earlier investigators have pointed out. 25 - 2G 

The active myelination process appears to 

occur for two to three weeks postnatally. 

Completion of the development of the

Volume 14 

Number 10 


optic nerve appears to be slightly later 

than that of the retinal tissue. 27 

The author is grateful to Drs. David G. Cogan 

and Jin H. Kinoshita for their continuous encouragement 

in this study. Miss Dorothy Drago's 

technical assistance is appreciated. 

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