Müller glia: Stem cells for generation and regeneration of retinal neurons in teleost fish

Abstract

Adult zebrafish generate new neurons in the brain and retina throughout life. Growth-related neurogenesis allows a vigorous regenerative response to damage, and fish can regenerate retinal neurons, including photoreceptors, and restore functional vision following photic, chemical, or mechanical destruction of the retina. Müller glial cells in fish function as radial-glial-like neural stem cells. During adult growth, Müller glial nuclei undergo sporadic, asymmetric, self-renewing mitotic divisions in the inner nuclear layer to generate a rod progenitor that migrates along the radial fiber of the Müller glia into the outer nuclear layer, proliferates, and differentiates exclusively into rod photoreceptors. When retinal neurons are destroyed, Müller glia in the immediate vicinity of the damage partially and transiently dedifferentiate, re-express retinal progenitor and stem cell markers, re-enter the cell cycle, undergo interkinetic nuclear migration (characteristic of neuroepithelial cells), and divide once in an asymmetric, self-renewing division to generate a retinal progenitor. This daughter cell proliferates rapidly to form a compact neurogenic cluster surrounding the Müller glia; these multipotent retinal progenitors then migrate along the radial fiber to the appropriate lamina to replace missing retinal neurons. Some aspects of the injury-response in fish Müller glia resemble gliosis as observed in mammals, and mammalian Müller glia exhibit some neurogenic properties, indicative of a latent ability to regenerate retinal neurons. Understanding the specific properties of fish Müller glia that facilitate their robust capacity to generate retinal neurons will inform and inspire new clinical approaches for treating blindness and visual loss with regenerative medicine.

Transgenic expression of the proneural transcription factor Ascl1 in Müller glia stimulates retinal regeneration in young mice

“…The response to damage in Ascl1-expressing Müller glia has some features in common with the response of these cells in the fish in that they down-regulate Rlbp1 and other glial genes, while increasing their expression of progenitor genes (33)(34)(35). However, in the zebrafish, the initial mitotic division of the Müller glia produces progenitor cells that continues to divide to generate new neurons (2,34), whereas in Ascl1-expressing mouse Müller glia, the amount of mitotic division is much lower, even with Ascl1 expression. Thus, additional factors will be required to produce a full regenerative response in adult mice more like that in fish.…”

“…reprogramming | glia | regeneration | neurogenesis | eye T he retina of the teleost fish has a remarkable potential to regenerate new neurons after various types of injury (1,2). This regenerative potential is much more limited in birds, where neurotoxic damage leads to regeneration of only a subset of inner retinal neurons.…”

Immunomodulation-accelerated neuronal regeneration following selective rod photoreceptor cell ablation in the zebrafish retina

“…Microglia of the human CNS also exhibit this phenomenon, although possibly exhibiting fewer differences between polarization states (27). Importantly, acutely activated microglia are known to express neuroprotective and regenerative factors, e.g., TGFβ, IGF1, IL-10, LIF, and MANF (74,78), some of which have been shown to stimulate MG proliferation (5,6). Combined, these observations suggest that after an initial reactive response to neuronal cell death microglia may adopt an antiinflammatory phenotype to stimulate stem/ progenitor cell proliferation.…”

The bHLH Transcription Factor NeuroD Governs Photoreceptor Genesis and Regeneration Through Delta-Notch Signaling

“…S4). However, by 7 dpl, when regenerated photoreceptors are exiting the cell cycle and differentiating, 29,60 pax6a is downregulated in all photoreceptors while neurod and nr2e3 are downregulated in newly postmitotic cones but continue to be expressed in rods (Supplementary Fig. S4).…”

“…[25][26][27][28][29][30][31][32][33] Recent studies in zebrafish have identified mechanisms that govern the Müller glia response to retinal injury, [34][35][36][37] but information is lacking around the pathways that govern photoreceptor regeneration from Müller glia-derived progenitor cells. The mechanisms that govern retinal regeneration are expected to largely recapitulate embryonic development, 28,29,38 though few molecules have been functionally studied during both events. NeuroD function has not been studied in the adult zebrafish retina, but following photoreceptor ablation neurod is expressed in Müller glia-derived mitotic progenitors, 39 suggesting that NeuroD has a role in photoreceptor regeneration.…”