Kenneth C. Wikler

Regressive events in brain development and scenarios for vertebrate brain evolution

The problems of the evolution of varying brain size, the specialization of particular functional systems and overall differences in the relative complexity of brain organization are discussed in terms of alterations of regressive events in neurogenesis (cell death and axon retraction). Three scenarios for evolution, cascade reorganization, parcellation and heterochrony, are considered in light of regressive mechanisms during development.

Early emergence of photoreceptor mosaicism in the primate retina revealed by a novel cone‐specific monoclonal antibody

We have examined the emergence of the photoreceptor mosaic in fetal macaque monkeys by using a novel monoclonal antibody, 7G6, that recognizes all cones in the adult primate retina. In the fetal retina, however, between embryonic (E) day 80 and E130, some opsin‐positive cones were not labeled by 7G6. Double‐labeling experiments revealed that though long and middle wavelength‐sensitive fetal cones are 7G6‐positive, a subset of short wavelength‐sensitive cones are delayed in their acquisition of 7G6 immunoreactivity. Heterogeneity in cone labeling with 7G6 was evident at all fetal ages. The onset of 7G6 immunoreactivity, surprisingly, precedes both the expression of the cone opsins and the formation of synaptic contacts in the outer plexiform layer. Specifically, a population of cones was labeled in the periphery of the E65 retina, concomitant with ongoing cone genesis. Moreover, early‐differentiating 7G6‐positive cones are organized into a regular array in immature, peripheral regions of the fetal retina indicating that the spatial arrangement of cones is initiated either during active cone proliferation or the initial differentiation of these cells. These results suggest that the periodic spacing of cones in the primate retina emerges autonomously within the photoreceptor layer, prior to the formation of synaptic connections within the retina or with the brain. J. Comp. Neurol. 377:500–508, 1997.

Positional information and opsin identity in retinal cones

To test the hypothesis that local environmental cues regulate the expression of middle wavelength‐sensitive (MWS) and short wavelength‐sensitive (SWS) opsins in cone photoreceptors, we examined the development of the neonatal mouse retina in an organotypic culture system. The segregation of MWS and SWS cones into dorsal and ventral fields in the mouse retina offers an opportunity to isolate a phenotypically homogeneous population of immature cones prior to opsin expression.

Retinoid-dependent gene expression regulates early morphological events in the development of the murine retina.

Endogenous retinoids have been implicated in the axial patterning of the embryonic vertebrate retina; however, no studies have directly examined how asymmetric retinoid‐dependent gene expression regulates early morphological events in the development of the retina. Here we used a line of indicator mice that possess a retinoid‐dependent transgene to examine the relationship between retinoic acid (RA)‐dependent gene expression and events occurring during early eye morphogenesis, such as the closure of the optic disc. We found that retinoid‐regulated gene expression shifts along the dorsal/ventral axis of the embryonic retina; at embryonic day (E) E11.5 transgene expression is restricted to the neuroepithelium in dorsal retina, and by E14.5 only immature cells located in ventral retina and the dorsal retinal margins demonstrate transgene activation. By manipulating RA levels, we were not only able to systemically alter RA‐dependent gene expression along the dorsal/ventral axis, but also to affect retinal morphology. In particular, reducing RA availability resulted in the abnormal closure of the optic fissure. These results indicate that asymmetric levels of RA regulate early RA‐dependent gene expression in the eye and demonstrate that the normal pattern of retinoid‐dependent gene transcription along the dorsal/ventral axis is critical for the proper development of the vertebrate retina. J. Comp. Neurol. 417:289–298, 2000.

Differential elasticity of the immature retina: A contribution to the development of the area centralis?

Differential stretch of a retinal surface with an initially uniform cell density has been repeatedly implicated as one of the developmental mechanisms that produces the topographic organization of cell density in the adult retina, notably the area centralis or visual streak versus peripheral regions. It is known that intraocular pressure is required to produce the normal conformation and thinning of the retina during development. We tested the possibility that the retina has elastic properties that might permit differential stretch in conjunction with intraocular pressure. The relative deformation of the retina containing the presumptive area centralis was compared to the deformation of peripheral retina at equivalent applied fluid displacements in 7-12-day-old cats. The peripheral retina deformed significantly more, consistent with the hypothesis that differences in the local elasticities of the developing neural retina contribute to its characteristic topographic changes. Thus, a biomechanical property of the growing eye may contribute to the mechanism by which the pattern of the visual array is sampled.

Control of cell number in the developing visual system. II. Effects of partial tectal ablation

The effects of potential excess innervation on cell survival in the superior colliculus and related structures during the period of normally occurring cell death was examined. A unilateral, partial lesion of the superficial layers of the superior colliculus on the day of birth, which results in a compression of the retinotectal map into the remaining area, was the manipulation used to produce the potential excess innervation. Cell density was reduced in the tectal fragment early in development, consistent with hyperinnervation, but had returned to normal by the end of the period of normally occurring cell death. The overall incidence of cell degeneration in the remaining partial colliculus was not different from the undamaged contralateral colliculus or from normal, though there was evidence of a transitory depression and later elevation of cell loss. Cell loss in the retina contralateral to the lesion was increased in the late part of the period of normal cell loss and there were fewer cells in the retinal ganglion cell layer at maturity. The amount of the cell loss in the retina was small compared to the amount of target removal. These results suggest that the survival of neurons with branching axons does not sensitively reflect target availability.

Developmental Heterochrony and the Evolution of Species Differences in Retinal Specializations

The vertebrate retina is relatively stable across phylogeny in the classes and types of cell that compose its radial organization. Mechanistic studies of development have described how aspects of retinal organization common to all retinas emerge, such as the control of neurogenesis of particular cell types, competitive control of cell survival and dendritic organization in the development of retinal lamination, and the mechanics of directed axon outgrowth. However, vertebrate eyes also differ markedly between species in overall size, shape, and resolving power as well as in the number and arrangement of cells in the retina. Thus, studies of retinal neurogenesis must account for the development of species differences in eye conformation and retinal organization and address the evolutionary regulation of these developmental programs.

Temporal retina is preferentially represented in the early retinotectal projection in the hamster.

Retrograde transport of horseradish peroxidase (HRP) after complete transection of the brachium of the superior colliculus on the day of birth in hamsters revealed preferential labelling of the temporal retina. Cytochrome oxidase staining of the retina showed similar preferential temporal labelling. A discrete lack of label of the extreme temporal periphery of the retina contralateral to the HRP placement and a complementary label of ipsilateral temporal periphery were also observed.