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Review
. 2014 May;40:94-123.
doi: 10.1016/j.preteyeres.2013.12.007. Epub 2014 Jan 8.

Müller Glia: Stem Cells for Generation and Regeneration of Retinal Neurons in Teleost Fish

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Free PMC article
Review

Müller Glia: Stem Cells for Generation and Regeneration of Retinal Neurons in Teleost Fish

Jenny R Lenkowski et al. Prog Retin Eye Res. .
Free PMC article

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.

Keywords: Adult neurogenesis; Müller glia; Radial glia; Retinal regeneration; Retinal stem cells.

Figures

Fig. 1
Fig. 1
Camera lucida drawings of the morphological differentiation of Müller glial cells in the embryonic chick retina. Panel 53. First stages of Müller glial cell differentiation in relation to retinal neurons. V, mitotic neuroepithelial (ventricular) cell; I, migrating, young ganglion cell; b, young bipolar cell; g, ganglion cell; a, amacrine cell; II, migrating amacrine cells; h, horizontal cell; f, photoreceptor cell; cf, centrifugal fibers; HH, Hamburger–Hamilton stages of chick embryo development. Panel 54. Last stages of Müller glial cell differentiation showing the central-peripheral gradient of differentiation. Reprinted with permission from Prada et al., 1989.
Fig. 2
Fig. 2
Neurogenesis in the adult teleost fish retina during growth and regeneration. Germinal zone with multipotent retinal stem cells and committed retinal progenitors (magenta) at the junction between the neural retina and the ciliary epithelium (CE). New retinal neurons are generated sequentially: first retinal ganglion cells (GC), then interneurons (amacrine cells, AC; bipolar cells, BP; horizontal cells, HC), then cone photoreceptors. The apical surface of the neural retina faces the retinal pigmented epithelium (RPE) at the back of the eye; the basal surface of the neural retina is vascularized (blood vessels, BV). Radial processes of Müller glial cells (green) span the apical-basal extent of the retina and lateral processes enwrap the neurons. Müller glia are somatic retinal stem cells supporting the rod lineage: they divide infrequently, with an asymmetric, self-renewing division, to give rise to proliferating, committed progenitors that migrate to the apical surface to generate rod photoreceptors within the differentiated retina. When retinal neurons are destroyed, microglia (MicG) are activated and remove cellular debris. The nuclei of Müller glia translocate to the apical surface, divide asymmetrically to give rise to proliferating, multipotent retinal progenitors that accumulate around the radial glial fiber and migrate to the appropriate retinal laminae to regenerate neurons (e.g., cone photoreceptors or retinal ganglion cells).
Fig. 3
Fig. 3
Müller-glia derived retinal progenitors migrate associated with the radial glial process. Serial section, electron microscopic (EM) autoradiography of Müller glia and the glial-derived rod photoreceptor progenitors in an early juvenile goldfish injected with 3H-thymidine and sacrificed 12 h later. Panel A) is a standard electron micrograph and B) is a nearby section in the serial set that was processed for autoradiography. The black “squiggles” represent the developed silver grains in the photographic emulsion overlying the section. The Müller glial nucleus (M) in the inner nuclear layer (INL) is recognized by its distinctive polygonal morphology and diffuse, pale chromatin. The rapidly dividing rod progenitors (P), which are labeled with 3H-thymidine in panel B, cluster around the radial fiber of the Müller glia, extending through the outer plexiform layer (OPL) into the outer nuclear layer (ONL), where the cell bodies and apical processes of photoreceptors (PR) reach to the retinal pigmented epithelium (RPE). C) Schematic drawing to illustrate the rod lineage – based on serial, EM reconstructions and longitudinal, 3H-thymidine autoradiography of Müller glial-derived, 3H-thymidine-labeled rod progenitors and differentiating rod photoreceptors. Reprinted with permission from Raymond and Rivlin (1987).
Fig. 4
Fig. 4
Overview of signaling pathways that regulate proliferation of Müller glia and Müller glia-derived progenitors during retinal regeneration in adult zebrafish. Following retinal injury, expression of factors associated with a stress response, inflammation, gliosis, and cell adhesion and migration are modified to regulate cell proliferation leading to regeneration of retinal neurons. Solid lines indicate regulatory interactions that have been described in the literature; dashed lines indicate suggested or indirect interactions. See Section 5 for references and further discussion of when and where these various factors are expressed during retinal regeneration.

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