RETINA REGENERATION

BACKGROUND:

Retinal regeneration: Until recently, it was thought that retinal regeneration was limited to lower, cold-blooded vertebrates, like fish and frogs. For example, fish and amphibians can regenerate their retinas almost perfectly and regain a high degree of normal function. Unfortunately, mammals (including humans) do not possess this capability, and so when the retinal ganglion cells are lost in degenerative disorders like glaucoma or photoreceptors in age-related macula degeneration, these neurons are not restored. However, a few years ago it was discovered that higher vertebrates, like birds, also possess some capacity for regeneration. In the posthatch chick retina, several types of neurotoxic injury can stimulate neural regeneration. Strikingly, in the last few years several groups have reported that at least some types of neurons can be regenerated in the mammalian retina in vivo or in vitro, and that regen erat ion of neurons can be stimulated using growth factors or transcription factors. So far two major cell types have been identified as sources for retinal regeneration – Müller glia and retinal pigment epithelium (RPE). If the retina is removed surgically or destroyed in some types of amphibians and in embryonic chick the RPE cells respond by reentering the mitotic cell cycle and dedifferentiated RPE expresses retinal progenitor genes. RPE derived progenitors recapitulate the sequence of embryonic retinogenesis. In embryonic chick a complete retina is generated, but the retinal structure is inverted. Similarly, amphibians regenerate a complete retina but with normal lamination and appropriate reconnection with central visual nuclei to restore visual function.


FUTURE RESEARCH GOALS:
How come mammals cannot regenerate most of their body parts? Newts might tell the tale why mice do fail.

Truth is we found a way to stimulate regeneration of mouse retinal neurons without seeking much advice from our aquatic friends. Nevertheless – this regeneration is very limited in the types and numbers of neurons regenerated. However studies on development, regeneration and disease from the last 50 years in zebrafish, goldfish, axolotl, newt, chicken and rodents led part of the way. At least one turning point towards a better understanding of the regeneration of the retina was that Müller glia were identified as the primary source cell for de-novo neurogenesis in the adult fish and bird – and as we now know in mice as well.

In our lab we seek to discover the mechanisms and roadblocks of retinal regeneration. Most specifically we are currently interested in the early induction mechanism of glia de-differentiation and cell cycle re-entry. In the adult retina some Müller glia undergo changes in their phenotype including but not limited to
changes in cell morphology and gene expression which may further lead to cell migration, soma displacement and cell proliferation. 







Upon application of specific growth factors Müller glia can be stimulated to proliferate and apparently only a small subset of Müller glia de-differentiates towards a progenitor-like phenotype that ultimately may lead to the de-novo neurogenesis (regeneration) of amacrine neurons in mice in vivo (see Karl MO et al. PNAS 2008 and Review Karl & Reh Trends Mol Med 2010).







FIGURES: (top) Drawing mouse & salamander. (middle) Regeneration Scheme Adult Mouse Retina: A small set of Müller glia (MG) de-differentiate into a proliferating progenitor like cell (pink) that may give rise to a limited number of new amacrine (red=AC) neurons in vivo. Picture of a BrdU labelled (cell proliferation label=red) newly regenerated GABAergic (GAD67-GFP=green) amacrine cell.