The influence of retino-tectal innervation on cell proliferation and cell migration in the optic tectum of the embryonic teleosts, Brachydanio rerio and Astyanax mexicanus, was investigated in a combined autoradiographic and experimental embryological study.

Unilateral eye Anlage removal was the method used to compare development of the affected non-optic-innervated tectum with that of its normal opposite innervated tectum.

The amount of mitosis as estimated by [3H]thymidine incorporation was not stimulated by retino-tectal innervation. Likewise no increase in cell number was found in the innervated tectum.

Cell migration and differentiation in the marginal zone was enhanced by retino-tectal innervation.

Conflicting results concerning proliferation, migration and differentiation in different species are explained by differences in time of ingrowth of the optic nerves and their depth of penetration into the tectum.

The optic tectum of the teleost offers an excellent model in which to study the effect of afferent innervation on the development of a nervous system centre. Retino-tectal axons from the retinal ganglion neurons of the developing eye grow into the mesencephalon very early in development. In less than 72 h of development, optic endings have reached the deepest layer of the subventricular zone of the developing optic tectum before significant tectal cell proliferation, differentiation and morphogenesis (cell migration and layer formation) have taken place (Schmatolla & Fischer, 1972). In a previous study it was shown that cell size and differentiation of neurons in the teleost tectum are dependent upon optic innervation (Schmatolla, 1972). This present study is concerned with the influence of etino-tectal innervation on cell proliferation and migration in this model.

Early removal of the optic Anlage, before retino-tectal connexions are established, enables one to compare development of the affected contralateral nonoptic-innervated tectum with that of its normal opposite innervated tectum. This method has been used by a number of investigators to examine the influence of optic innervation on tectal development in a variety of species with conflicting results. In fish Pflugfelder (1952), studying Xiphophorus and Lebistes, found no change in tectal cell number, but reported an increase in nuclear size in the innervated tectal side. White (1948) in Fundulus, however, found an increase in cell number in the innervated side, but made no comment as to change in cell size. Neither investigator made observations as to differences in mitotic activity or cell migration. In amphibians, Kollros (1953) in Rana pipiens and Larsell (1929, 1931) in Hyla regilla reported an increase in cell number in the superficial tectal layers of the innervated side, but they made no attempt to count cell numbers in the deep tectal layers. Kollros reported an increase in mitosis in the innervated side. Eichler (1971) in Rana pipiens found no difference in cell size in the innervated side, whereas Larsell (1931) in Hyla regilla observed an increase in cell size. Eichler reported increased mitosis in the innervated side as well as increase in cell number in all tectal layers. In the chick Filogamo (1950) described no differences in the development of the tectum up to the 12th day of development in the affected side; after the 12th day he reported a decrease in cell number on the affected side. Kelly & Cowan (1972) found no effect of ‘deafferentation’ upon cell differentiation, cell proliferation or migration in the chick tectum up to the 14th day of development, but thereafter report a considerable degree of cell loss in the affected side. Cowan, Martin & Wenger (1968) found no effect of early eye removal on the mitotic rate in the chick tectum.

During our previous study in the teleost (Schmatolla, 1972) we observed that even though the affected optic lobe was smaller than the control side, largely due to the poor dendrite development and absence of optic fibres, its cells were smaller and more closely packed, suggesting the possibility that there may be no difference or perhaps even an increase in cell number. In view of the conflicting conclusions of the reports of Pflugfelder (1952) and of White (1948), and differences observed in other species, we felt that the influence of retino-tectal innervation on cell proliferation in the teleost required further clarification.

The early works of Larsell and Kollros cited above are partly responsible for the prevalent idea that innervation of the tectum by optic fibres stimulates proliferation. Since they only counted cells in the peripheral layers of the tectum, the noted increase in cell number may have been a reflexion of an increase in cell migration into the marginal zone on the innervated side, with total cell number being unaffected. For this reason, in addition to evaluating the effect of innervation on cell number in the sub ventricular zone, we also report on its effect on cell number in the marginal zone of the embryonic tectum. Our results indicate that in the teleost, optic innervation does not promote cell proliferation, and on the contrary may even inhibit it, but innervation does appear to increase cell migration into the marginal zone.

The amount of mitosis was considered to be represented by the number of cells labelled with [3H]thymidine in autoradiographs. For this purpose, eye Anlage were removed unilaterally from 24 Brachydanio rerio embryos, 30–36 h old, as previously described (Schmatolla, 1972). Each 24 h, from 48 h to the 10th day of development, at least two of the eye-extirpated embryos were injected into the cardiac region with 0·05 μ Ci of [3H]thymidine methyl, sp. act. 6·7 Ci/mM in 0·001 μ I of aqueous solution. After 24 h following injections, each group of embryos was killed and fixed in Carnoy’s solution for 4h. After fixation the specimens were embedded in paraffin, and transverse sections at 5 /<m thickness were made serially through the entire optic tectum. Following routine processing of the paraffin sections, autoradiographs were made with Ilford L4 emulsion employing the dipping technique of Kopriwa & Leblond (1962). Exposure time varied from 8 to 12 days. The autoradiographs were developed with Kodak D 19b at 20 °C for 6 min, fixed, and permanently mounted with Eukitt (O. Kindler, Freiburg, West Germany). Labelled cells in the serial sections were counted in unstained autoradiographs with the aid of phase-contrast microscopy.

For the evaluation of cell number in the subventricular zones of 1-week-old embryos, one Astyanax mexicanus and two Brachydanio rerio embryos, each with one eye extirpated, were used. These were routinely embedded in paraffin, stained with haematoxylin and eosin, and cut at 7 μm thickness. Photomicrographs were taken at ×400 of each serial section comprising the total tectal length of each animal - a total of 111 photographs. These were enlarged to an 18 × 24 cm format, and with the aid of the automatic marker and counter of the Zeiss TGZ 3 Particle Size Analyser, all cells in the innervated and affected tectal sides were counted.

Marginal cell numbers were obtained by counting all cells in the tectal peripheral white matter (marginal zone) in serial sections of embryos whose optic Anlage were removed at 30–36 h of development. The counts were done from photomicrographs taken at ×400 of the serial sections in specimens 4, 7, 20, 14, 28 and 42 days old.

Since the actual cell counts included cells and fragments of cells, and because cells in the non-innervated tecta were smaller than those in the innervated tecta, the numbers of cells reported in the results represent cell counts corrected by the application of the formula of Abercrombie (1946). The differing cell sizes used in the calculations were derived from the previously published study on cell differentiation in these fishes (Schmatolla, 1972).

The specimens reported on for evaluation of the cell number in the subventricular zone, and the cell number in the marginal zone, were from the same groups reported in the above study on cell differentiation.

Effect of innervation on mitosis

In the teleost optic tectum mitosis is confined to well-demarcated areas of the embryonic grey matter. As described by Kirsche (1960) and by Richter & Kranz (1970), and confirmed by our observations in both haematoxylin stained specimens and in [3H]-thymidine-labelled preparations, these regions, the so-called ‘matrix zones’, consist of (1) a dorsal matrix zone in the medial tectal corner, (2) a basal matrix zone in the lateral tectal corner, and (3) a caudal matrix zone which represents the union of the above two zones in the caudal region of the tectum (Fig. 1). The overall ependymal zone does not produce new cells, and mitosis was not seen in the subventricular zone outside the matrix zones. No mitosis was seen in the cells that had migrated out of the subventricular zone into the marginal zone.

FIGURE 1

(A) Autoradiograph of transverse section through mid-tectum of 3-day-old Brachydanio rerio embryo showing [3H]thymidine-labelled dorsal matrix zone (dmz) and basal matrix zone (bmz). [3H]Thymidine, 0·05 μ Ci given at 48 h of age, embryo killed 24 h later. (B) Caudal section through same tectum showing caudal matrix zone (cmz). Unstained, phase-contrast.

FIGURE 1

(A) Autoradiograph of transverse section through mid-tectum of 3-day-old Brachydanio rerio embryo showing [3H]thymidine-labelled dorsal matrix zone (dmz) and basal matrix zone (bmz). [3H]Thymidine, 0·05 μ Ci given at 48 h of age, embryo killed 24 h later. (B) Caudal section through same tectum showing caudal matrix zone (cmz). Unstained, phase-contrast.

Following [3H]thymidine injections from the 2nd to the 8th day of development, the number of labelled cells at sacrifice 24 h later are shown in Table 1 and Fig. 2. The total number of labelled cells seen at each day of development represents the sum seen in serial sections of the entire tecta in the three matrix zones. Generally the most obvious difference in the number of labelled cells between the control and affected side was seen in the basal matrix zone and in the rostral portion of the caudal matrix zone.

Table 1.

Comparison of number of cells labelled with [3H]thymidine in matrix zones of optic tecta following unilateral eye Anlage extirpation in Brachydanio rerio embryos*

Comparison of number of cells labelled with [3H]thymidine in matrix zones of optic tecta following unilateral eye Anlage extirpation in Brachydanio rerio embryos*
Comparison of number of cells labelled with [3H]thymidine in matrix zones of optic tecta following unilateral eye Anlage extirpation in Brachydanio rerio embryos*
Fig. 2.

Effect of early eye removal on number of [3H]thymidine-labelled cells in matrix zones in embryonic tecta of Brachydanio rerio. Note slight increase in mitosis in non-innervated side. The data graphically represented here are derived from Table 1. The dots for days 4, 5, 6 and 7 represent mean figures. • — •, Absent retino-tectal innervation. ○ – – ○, Control contralateral side.

Fig. 2.

Effect of early eye removal on number of [3H]thymidine-labelled cells in matrix zones in embryonic tecta of Brachydanio rerio. Note slight increase in mitosis in non-innervated side. The data graphically represented here are derived from Table 1. The dots for days 4, 5, 6 and 7 represent mean figures. • — •, Absent retino-tectal innervation. ○ – – ○, Control contralateral side.

Inspection of the curves in Fig. 2 shows that by the 9th day of development very few labelled cells were present. From observations on older embryos in material stained with haematoxylin and eosin, mitosis was never seen in the matrix zones of Brachydanio after the 10th day of development.

Of the 12 experimental animals, 11 showed more labelled cells in the noninnervated side, with an over-all increase in the entire series of 13·8% on the affected side. The 3-day-old animal might be expected to show little effect of optic innervation, since at 72 h the optic nerve has been in the tectum for less than 24 h. It is difficult to determine how significant a 13·8 % increase in labelled cells should be considered, but these data certainly suggest that mitosis is not greater on the innervated side, and may actually be less.

Effect of innervation on cell number in the subventricular zone

Tectal cell number was evaluated in 1-week-old Brachydanio rerio and Astyanax mexicanus embryos following unilateral eye removal. In the embryonic tectum at this age the vast majority of cells are confined to the so-called sub-ventricular zone. Only a small percentage of cells (less than 10 %) have migrated out into the marginal zone (Fig. 3). In three embryos whose eye Anlage were removèd unilaterally before optic nerve development, all cells were counted in serial sections of the entire tecta on both sides. Casual inspection of a mid-tectal section of one of these embryos was enough to distinguish the affected side from the control side (Fig. 3). In addition to the reduction in overall size of the affected side, its cells appeared smaller, more tightly packed and more numerous. This difference could be seen as early as the 3rd day of development, and persisted well into the post-embryonic period at 6 weeks, at which age our observations were terminated (Figs. 4, 5). However, inspection of the caudal ends of the tecta did not reveal this consistently distinct difference in appearance. The counts of subventricular cells up to the caudal end of the tectum (Table 2) showed that there were between 18 % and 20% more cells in the affected side at 1 week of age. But when counts of the subventricular cells of the caudal ends, and of the marginal cells, were added in, the difference in cell number was not so striking, varying from 4·7 % to 11·1%. The chief point to emerge from these data is that one can say with some certainty that the number of cells in the innervated side was not increased, but actually may have been slightly decreased.

Table 2.

Comparison of cell number in affected and control optic tecta in 1-week-old teleost embryos following unilateral eye Anlage extirpation*

Comparison of cell number in affected and control optic tecta in 1-week-old teleost embryos following unilateral eye Anlage extirpation*
Comparison of cell number in affected and control optic tecta in 1-week-old teleost embryos following unilateral eye Anlage extirpation*
Fig. 3.

One-week-old Astyanax mexicanus, transverse section through mid-tectum. Non-innervated tectum (non-inn) is overall smaller than the innervated (inn), its cells in the subventricular zone (subv) are smaller and more numerous, and there are fewer cells (at arrows) in the marginal zone (marg). H and E.

Fig. 3.

One-week-old Astyanax mexicanus, transverse section through mid-tectum. Non-innervated tectum (non-inn) is overall smaller than the innervated (inn), its cells in the subventricular zone (subv) are smaller and more numerous, and there are fewer cells (at arrows) in the marginal zone (marg). H and E.

FIGURE 4.

Six-week-old Brachydanio rerio; transverse section through mid-tectum. Bodian stain. (A) Innervated side (inn) is larger than non-innervated side (non-inn), its marginal zone contains more cells (at arrows) than affected side. (B) Higher magnification of marginal zone of innervated side. (C) Higher magnification of marginal zone of non-innervated side. Note larger and more numerous marginal cells in innervated side.

FIGURE 4.

Six-week-old Brachydanio rerio; transverse section through mid-tectum. Bodian stain. (A) Innervated side (inn) is larger than non-innervated side (non-inn), its marginal zone contains more cells (at arrows) than affected side. (B) Higher magnification of marginal zone of innervated side. (C) Higher magnification of marginal zone of non-innervated side. Note larger and more numerous marginal cells in innervated side.

Fig. 5.

Cells in subventricular zones of same animal as in Fig. 4. Cells in innervated side (A) are larger and more loosely packed than in the subventricular zone of the non-innervated side (B), where they are smaller and more numerous. Bodian stain.

Fig. 5.

Cells in subventricular zones of same animal as in Fig. 4. Cells in innervated side (A) are larger and more loosely packed than in the subventricular zone of the non-innervated side (B), where they are smaller and more numerous. Bodian stain.

In the embryonic stages cells migrate out of the subventricular zone to populate the marginal zone. The resultant teleost adult tectum consists of a densely cellular stratum griseum periventriculare containing the residual majority of cells that did not migrate out of the embryonic subventricular zone, and a number of rather sparsely cellular and poorly demarcated layers formed by these migrated cells (Leghissa, 1955; Schmatolla, 1972). Our observations show that in Brachydanio, as early as the 4th day of development, there is an increase in the number of marginal cells in the innervated side as compared to the noninnervated side. This difference is clearly maintained through the embryonic and early juvenile period of development (Table 3 A). Mitosis was never seen in either side in the cells in the marginal zone. In addition to an increase in the number of marginal cells in the innervated side, there was also noted a distinct increase in their fibre development and cell and nuclear size (Fig. 4B, C), indicating better differentiation of these cells over their counterparts in the noninnervated tectum. In general, the marginal cells in the innervated tectum tended to migrate in greater numbers to the very superficial margin of the tectum. In the affected side the marginal cells remained more restricted to the inner two-thirds of the marginal zone.

Table 3.

Effect of retino-tectal innervation on marginal cell number

Effect of retino-tectal innervation on marginal cell number
Effect of retino-tectal innervation on marginal cell number

In Table 3B is demonstrated the effect of the absence of retino-tectal innervation on marginal cell number in the 1-week-old Astyanax mexicanus embryo. The percentage increase in marginal cell number due to innervation is of the same magnitude as in Brachydanio. The blind cave Astyanax hubbsi, the naturally occurring closely related Astyanax whose tectum contains no optic fibres (Schmatolla, 1972), offers an opportunity to compare the effects of the natural absence of innervation to that of extirpation of the eye in Astyanax mexicanus. Here too, as seen in Table 3B, innervation in the A. mexicanus tectum results in an increase in marginal cell number over the non-innervated tectum of the cave fish.

A conservative interpretation of our data regarding the effect of retino-tectal innervation in the teleost tectum on mitosis would indicate that innervation does not stimulate mitosis. Actually the data suggest that mitosis is slightly retarded in the matrix zones of the innervated tecta. From our previous study in which we demonstrated that the neurons in the innervated tectum of the teleost are better differentiated than those in the non-innervated tectum, one could speculate that innervation stimulates differentiation, which in turn inhibits mitosis. This is consistent with the observation that differentiated neurons loss their capacity to undergo mitosis. However, it may also be plausible that innervation inhibits mitosis, which then allows the no-longer-dividing cell to differentiate.

The experiments of Kirsche & Kirsche (1961) and Richter (1968) on regeneration of the optic tectum in teleost fish are of interest in relation to the effect of tectal innervation on matrix-zone activity. These investigators destroyed large portions of the optic tecta of juvenile and adult Carassius and Lebistes teleosts, and showed that an increase in the mitotic activity of the matrix zones occurred which was followed by tectal regeneration. In effect, the destruction of the tectum resulted in an interruption of retino-tectal innervation, resulting in deafferentation and concomitant increase in the mitotic activity of the matrix zones, which is in some respects similar to our observation of increase in mitotic activity in the matrix zones in our non-innervated tecta. It is of course unclear whether retino-tectal innervation has a direct effect through contact with cells in the matrix zones, or whether some other mechanism is involved.

Richter (1968) found mitotic activity in the matrix zones of adult Lebistes, whereas Rahmann (1968) found no mitotic activity in the matrix zones of juvenile and adult Brachydanio rerio. Our findings in Brachydanio also indicate that mitotic activity ceases in this species in the late embryonic period. It would be of interest to see if regeneration, and the activity of mitosis in the matrix zones would be stimulated by tectal resection in Brachydanio.

In our experimental material it may be of significance that the basal matrix zone, in the lateral corner of the embryonic tectum, was observed to be most affected by tetino-tectal innervation, since it is through this area that the optic fibres enter in the greatest portion of the teleost tectum.

In the chick, in a study of the effects of early eye removal (2nd day of development), Cowan et al. (1968) conclude that innervation has no effect on tectal mitosis. Here species differences play an important role. This result was to have been expected since optic-fibre penetration of the stratum opticum of the chick tectum does not take place until after the 10th day of development (Kelly & Cowan, 1972), by which time mitosis has virtually ceased as shown by the [3H]thymidine incorporation studies of Fujita (1964). Therefore the conclusion that early eye removal has no effect on tectal mitosis in the chick tectum is irrelevant, for comparing mitosis in a normal side to an ‘affected’ side has no meaning since both sides have no retino-tectal innervation until after mitosis has almost ceased.

Cell numbers in the subventricular zones in control versus affected tecta parallel the effects on mitosis. With a good deal of certainty one can say that there is no increase in cell number on the innervated side; actually the data suggest that cell number may be increased in the non-innervated side. This would be expected if the mitotic activity is also greater.

The clear increase in number of cells seen in the rostral portion of the rectum up to the caudal end in the affected side, as contrasted to the inconsistent findings in the caudal end, suggests a regionalized effect. Optic fibres in the fish embryo enter the tectum in the lateral-rostral portion of the optic lobes, and spread medially and caudally, with the caudal end last to be innervated. It is possible that much of the caudal ends on both sides never develops retino-tectal innervation. This remains to be clarified.

The fact that proliferation takes place at least equally as well in the noninnervated side demonstrates that tectal cell proliferation in the teleost is independent of retino-tectal innervation. Our cell counts were made in early embryos for we were interested in the effect of innervation on early cell proliferation. It is possible that observations on older animals following deafferentation would show more cells in the innervated side due to failure of trophic maintenance in the non-innervated side.

The most plausible conclusion to be drawn from the clear increase in marginal cell number in the innervated tectum would be that the presence of retinotectal innervation promotes migration out of the subventricular zone. That mitotic figures or incorporation of [3H]thymidine was never seen in these cells in the marginal zone is evidence against the possibility that the increase in marginal cell number was due to local proliferation after the cells had migrated out. Cell death as seen in the later stages of development in the chick deafferentated tectum (Filogamo, 1950; Kelly & Cowan, 1972) is not a likely explanation for the differences in marginal cell numbers reported here, since these differences seen in the teleost occur very early in development, and are greater in the younger than in the older specimens (Table 3). The marginal cells in the innervated side are distinctly larger and have better fibre development than those in the non-innervated side, paralleling our previous findings on the promotion of differentiation by innervation within the subventricular zone (Schmatolla, 1972).

How retino-tectal innervation stimulates the outward migration is unknown, but several possibilities exist. Since the retino-tectal fibres themselves penetrate the entire marginal zone to enter the subventricular zone perpendicularly, they offer a scaffold of fibres which can guide migrating cells and support their movement. Also, the subventricular cells in the innervated side differentiate more completely and send apical dendrites perpendicularly into the marginal zone which could also aid in migration. A somewhat similar mechanism of the reliance of migration on orientation of fibres has been proposed by DeLong & Sidman (1970) in discussing the failure of granule cell migration through the disorganized malaligned Purkinje cell layer in the reeler mutant mouse. And lastly, it may be that these better-differentiated cells have intrinsically a better mobility.

Species differences appear to play a great role in explaining the conflicting findings in the literature concerning the relationship of optic innervation to tectal development. For example, Larsell (1931) in Hyla found an increase in cell size in the innervated tectum, whereas Eichler (1971) in Rana found no difference. Both report finding an increase in cell numbers in innervated tecta. In the teleost we have found an increase in cell size in the innervated tectum (Schmatolla, 1972), but no increase in cell number, only an increase in cell migration. Kollros (1968) comments, in relation to these points of species differences, and limiting his discussion to anurans : ‘… [upon] the potential variability of the regulating mechanisms [between species]. In the optic tectum, for example, the regulation of tectal size in response to the absence of eye is dependent upon control of mitotic rate in some species, upon regulation of cell size in another, upon production and then later degeneration of cells in a third, while in a fourth type cell production is unaffected but only a fraction of the usual cell number undergoes maturation. The findings of inconsistencies between different anuran species need not be unexpected.’ Certainly one may consider these points to be even more applicable to the differences seen between anurans and teleosts.

In the chick, from the recent work of Kelly & Cowan (1972), it is apparent that cell proliferation, differentiation, cell migration and stratification of the tectum is rather well completed by the 12th day of development when the optic fibres penetrate the tectum, so that one can clearly say that these phenomena are not dependent upon retino-tectal innervation. But in the teleost, whose tectum is innervated very early in development, during the 3rd day, differentiation and cell migration are dependent upon retino-tectal innervation, but cell proliferation, as in the chick, appears to be an independent process, possibly even hindered by innervation and differentiation.

Between the chick, and the teleosts we have investigated, the important variable accounting for the differences in findings is relatable to the developmental behaviour of the optic nerves. In the teleost the optic fibres grow into the tectum early and penetrate to its depths, while in the chick they grow in late and end in the superficial regions. For this reason we feel that the teleost offers advantages with which to analyse the dependence of tectal development on optic innervation. The chick, while a poor model for this purpose, raises other questions, such as what are the driving mechanisms behind its tectal development if not optic innervation?

The authors wish to thank Lotte Ostertag for her assistance in the preparation of the histological material.

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