The chicken retina is capable of limited regeneration. In response to injury, some Müller glia proliferate and de-differentiate into progenitor cells. However, most of these progenitors fail to differentiate into neurons. The Notch pathway is upregulated during retinal regeneration in both fish and amphibians. Since the Notch signaling pathway maintains cells in a progenitor state during development, we hypothesized that a persistently active Notch pathway might prevent a more successful regeneration in the chick retina. We found that Notch signaling components are upregulated in the proliferating progenitors. We also found that blocking the Notch pathway while Müller glia are de-differentiating into progenitor cells prohibits regeneration; conversely, blocking the Notch pathway after the progenitors have been generated from the Müller glia caused a significant increase in the percentage of new neurons. Thus, Notch signaling appears to play two distinct roles during retinal regeneration. Initially, Notch activity is necessary for the de-differentiation/proliferation of Müller glia, while later it inhibits the differentiation of the newly generated progenitor cells.

The possibility of neural regeneration has gained credence with the identification of neural stem cells seeded within different regions of the adult central nervous system (CNS). Recently, this possibility has received an additional boost from reports that glia, the support cells of the CNS, might provide a source of neural regeneration. We review some of our findings that Mü ller glia in the chicken retina are a source of proliferating progenitors that can generate neurons. These Mü ller cells are fully differentiated glial cells that serve functions ascribed to this cell type. In response to damage or exogenous growth factors, Mü ller glia dedifferentiate, proliferate, express combinations of transcription factors normally expressed by embryonic retinal progenitors, and produce new neurons and glia. In light of these data, the potential of Mü ller glia as a source of neural regeneration in the retina of nonavian species, namely humans, seems an avenue of investigation that warrants serious consideration. GLIA 43:70 -76, 2003.

The addition of a third eye primordium to the forebrain region of a Rana pipiens embryo invariably results in the development of a series of periodic, mutually exclusive eye-specific bands in tectal lobes dually innervated by the host and supernumerary fibers. A number of investigators have proposed that such source-specific segregation arises as a compromise between two mechanisms that are normally involved in retinotectal map formation: one which is dependent on cell surface affinities to align the map and produce a rough retinotopy and a second that "fine tunes" the map by stabilizing adjacent terminals from neighboring retinal ganglion cell bodies at the expense of terminals from non-neighboring cells. In this study we have tested the idea that this second "fine-tuning" mechanism is dependent on neural activity by blocking impulse activity in the optic nerves of three-eyed tadpoles. To assess the requirement for activity on the formation of bands, both normal optic nerves of 17 three-eyed tadpoles were crushed intraorbitally. Two weeks after this operation, the supernumerary retinal projection had debanded and spread to cover the entire tectum in a continuous fashion. By 4 weeks, however, the host optic fibers regenerated back to the tecta and began to form segregated stripes with the fibers from the third eye. Six to 7 weeks after the optic nerve crush the periodic pattern of eye-specific segregation characteristic of dually innervated tecta was again pronounced. When activity in all three optic nerves was eliminated with tetrodotoxin (TTX; embedded in a slow release plastic) during the last 3 weeks of this process, the fibers from the two competing eyes failed to segregate and, instead, formed two completely overlapping, continuous projections across the tectal surface. To test for the requirement of activity in the maintenance of segregation, we also subjected three-eyed tadpoles without optic nerve crush to TTX blockade for 2, 3, and 4 weeks. Animals sacrificed at 2 weeks show overlap of the projections in the rostral tectum but distinct interdigitating stripes in other regions of these lobes. After 3 weeks of blockade, segregation of the projections was less distinct in the central tectum as well. After 4 weeks of TTX blockade the terminals from both eyes spread to form continuous overlapping projections throughout the tectum. Examination of well isolated, individual retinal ganglion cell terminal arbors during this period reveals that they occupy a significantly greater area of tectum following the TTX treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

Neuronal degenerations in the retina are leading causes of blindness. Like most other areas of the CNS, the neurons of the mammalian retina are not replaced following degeneration. However, in nonmammalian vertebrates, endogenous repair processes restore neurons very efficiently, even after complete loss of the retina. We describe the phenomenon of retinal regeneration in nonmammalian vertebrates and attempts made in recent years to stimulate similar regenerative processes in the mammalian retina. In addition, we review the various strategies employed to replace lost neurons in the retina and the recent use of stem cell technologies to address problems of retinal repair.

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Progenitor cells isolated from early rat embryo retinas differentiate into phenotypes normally generated early in retinal development (e.g., ganglion cells), whereas progenitors isolated from postnatal retinas differentiate into later-generated retinal cell types (e.g., rod photoreceptors; Reh and Kljavin, J. Neurosci. 9:4179-4189; 1989; Adler and Hatlee, 1989; Science 243:391-393; Sparrow, Hicks, and Barnstable, 1990, Dev. Brain Res. 51:69-84). To determine whether this change in committment is intrinsic to the progenitor cells, or alternatively can be modified by interactions with their developing environment, I co-cultured mouse and rat retinal cells, from different developmental stages, and identified the resulting phenotypes with species-specific and cell class-specific antibodies. I found that the phenotypes into which mouse neuroepithelial cells differentiate depends on the phenotypes of the rat cells that surround them. Retinal precursor cells from embryonic day (E) 10-12 will adopt the rod photoreceptor phenotype only when close to cells expressing this phenotype. By contrast, when the E10-12 retinal progenitor cells are cultured with cells from the cerebral cortex, they differentiate primarily into large multipolar neurons, similar in their morphology and antigen expression to retinal ganglion cells. These results indicate that interactions among the cells of the developing retina are important in the determination of cell fate.

The sensory reception of vision, olfaction, hearing and balance are mediated by receptors that reside in specialized epithelial organs. Age-related degeneration of the photoreceptors in the retina and the hair cells in the cochlea, caused by macular degeneration and sensorineural hearing loss, respectively, affect a growing number of individuals. Although sensory receptor cells in the mammalian retina and inner ear show only limited or no regeneration, in many non-mammalian vertebrates, these sensory epithelia show remarkable regenerative potential. We summarize the current state of knowledge of regeneration in the specialized sense organs in both non-mammalian vertebrates and mammals, and discuss possible areas where new advances in regenerative medicine might provide approaches to successfully stimulate sensory receptor cell regeneration. The field of regenerative medicine is still in its infancy, but new approaches using stem cells and reprogramming suggest ways in which the potential for regeneration may be restored in individuals suffering from sensory loss.

Interconnecting neuronal populations in the vertebrate CNS are typically not well matched in their overall topographic patterns of histogenesis and differentiation during development. One striking example of this mismatch is the retinotectal system of the frog, where the retina grows in concentric annuli, while the optic tectum, a major retinal target, adds new neurons at only the caudo-medial border. The retinal ganglion cell (RGC) terminals nevertheless form an organized map in the tectum during the period when the two structures are undergoing such disparate modes of growth. This led Gaze et al. (Gaze, R. M., M. J. Keating, and S. H. Chung (1974) Proc. R. Soc. Lond. (Biol.) 185: 301-330) to propose that the terminals must shift caudally during development. In the present study, we have directly tested the hypothesis of "shifting connections" by selectively labeling an identified population of RGC terminals, those at the optic nerve head (ONH), and determining their tectal projection site relative to a particular group of [3H]thymidine-labeled tectal neurons. With this double-label technique, we have found that RGC terminals from cells at the ONH move from a position rostral to the [3H]thymidine-labeled tectal cells to a position caudal to these same cells during the latter half of larval development. This represents a movement of approximately 1.4 mm across the tectal surface between stages T&K XII and T&K XXV. In addition, we have used electron microscopy and electrophysiology to demonstrate that the RGC terminals make functional synaptic connections during this period. This indicates that RGC terminals continually change the tectal neurons with which they form functional synapses during the development of the retinotectal system. We propose that such moving, but highly ordered connections can best be explained by a two stage mechanism for map formation, in which graded selective adhesions between cells in appropriate regions of retina and tectum provide the overall gross retinotopy of the projection, while competitive interactions between RGC terminals are responsible for the refinement of the precision in this system.