We have reported previously that neurotoxic damage to the chicken retina causes Müller glia to dedifferentiate, proliferate, express transcription factors common to retinal progenitors, and generate new neurons and glia, whereas the majority of newly produced cells remain undifferentiated (Fischer and Reh, 2001). Because damaged retinal cells have been shown to produce increased levels of insulin-related factors and FGFs, in the current study we tested whether intraocular injections of growth factors stimulate Müller glia to proliferate and produce new neurons. We injected growth factors and bromodeoxyuridine into the vitreous chamber of the eyes of chickens and assayed for changes in glial phenotype and proliferation within the retina. Although insulin or FGF2 alone had no effect, the combination of insulin and FGF2 caused Müller glia to coexpress transcription factors common to retinal progenitors (Pax6 and Chx10) and initiated a wave of proliferation in Müller cells that began at the retinal margin and spread into peripheral regions of the retina. Most of the newly formed cells remain undifferentiated, expressing Pax6 and Chx10, whereas some differentiate into Müller glia, and a few differentiate into neurons that express the neuronal markers Hu or calretinin. There was no evidence of retinal damage in eyes treated with insulin and FGF2. We conclude that the combination of insulin and FGF2 stimulated Müller glia to dedifferentiate, proliferate, and generate new neurons. These findings imply that exogenous growth factors might be used to stimulate endogenous glial cells to regenerate neurons in the CNS.

RXRgamma is essential (along with TRbeta2) for suppressing S-opsin in all immature cones and in dorsal cones in the mature retina, but it is not necessary for M-opsin regulation. These results demonstrate a critical role for RXRs in regulating cell differentiation in the CNS and highlight a remarkable conservation of opsin regulation from Drosophila to mammals.

No abstract

The ciliary marginal zone (CMZ) has long been known to be a source of postembryonic neuronal production in the retinas of fish and amphibians, and more recently, birds. However, there is little known about the factors that are required for the maintenance of this neural stem cell zone. The cells of the CMZ respond to mitogens such as endothelial growth factor, insulin-like growth factor-1, and insulin, factors that are also mitogenic for embryonic retinal progenitors, suggesting that the continued expression of embryonic mitogenic factors might be required to maintain the postembryonic proliferative potential of the CMZ. To test this hypothesis, we examined the expression and functional role of a critical embryonic retinal progenitor mitogen, Sonic hedgehog (Shh) in the regulation of proliferation of the cells of the CMZ. We have found that Shh is concentrated at the retinal margin of postembryonic chicks. Moreover, we report that intraocular injection of Shh stimulates proliferation of the CMZ cells, whereas cyclopamine, an inhibitor of the Shh pathway, inhibits CMZ proliferation. We conclude that Shh signaling is an important factor in the maintenance of postembryonic retinal neurogenesis. Developmental Dynamics 233:66 -75, 2005.

FGF signaling has been implicated as an important regulator of retinal development. As a first step in characterizing potential downstream targets of FGF signaling in the retina, we have analyzed expression of Pea3, a member of the Pea3 class of Ets-domain transcription factors, in the developing eye. We find that Pea3 is expressed in the developing retina, and its transcription is regulated by FGF receptor activation. In addition, FGF signaling activates Cath5, a gene necessary for retinal ganglion cell differentiation. These results suggest that FGF signaling via MAPK up-regulates transcription factors that in turn control retinal ganglion cell differentiation. Developmental Dynamics 235:327-335, 2006.