Müller Glia, Vision-Guided Ocular Growth, Retinal Stem Cells, and a Little Serendipity

Abstract

Hypothesis-driven science is expected to result in a continuum of studies and findings along a discrete path. By comparison, serendipity can lead to new directions that branch into different paths. Herein, I describe a diverse series of findings that were motivated by hypotheses, but driven by serendipity. I summarize how investigations into vision-guided ocular growth in the chick eye led to the identification of glucagonergic amacrine cells as key regulators of ocular elongation. Studies designed to assess the impact of the ablation of different types of neurons on vision-guided ocular growth led to the finding of numerous proliferating cells within damaged retinas. These proliferating cells were Müller glia-derived retinal progenitors with a capacity to produce new neurons. Studies designed to investigate Müller glia-derived progenitors led to the identification of a domain of neural stem cells that form a circumferential marginal zone (CMZ) that lines the periphery of the retina. Accelerated ocular growth, caused by visual deprivation, stimulated the proliferation of CMZ progenitors. We formulated a hypothesis that growth-regulating glucagonergic cells may regulate both overall eye size (scleral growth) and the growth of the retina (proliferation of CMZ cells). Subsequent studies identified unusual types of glucagonergic neurons with terminals that ramify within the CMZ; these cells use visual cues to control equatorial ocular growth and the proliferation of CMZ cells. Finally, while studying the signaling pathways that stimulate CMZ and Müller glia-derived progenitors, serendipity led to the discovery of a novel type of glial cell that is scattered across the inner retinal layers. (Invest Ophthalmol Vis Sci. 2011;52:7705-7710)

The chick eye in vision research: An excellent model for the study of ocular disease

“…Some of the endogenous signaling molecules (reviewed by Wallman and Winawer (2004)) that have been determined to be involved in chick vision-guided eye growth and myopia development include dopamine (Lauber, 1991; Stone et al, 1989), gamma-aminobutyric acid (GABA) (Chebib et al, 2009; Christian et al, 2013; Stone et al, 2003), insulin-like growth factor-1 (IGF1) and fibroblast growth factor-2 (FGF2) (Ritchey et al, 2012b), N -methyl-D-aspartic acid (NMDA) (Fischer et al, 1998; Fischer et al, 1997), retinoids (Fischer et al, 1999b), and glucagon (Feldkaemper and Schaeffel, 2002; Fischer et al, 1999c; Fischer, 2005; Fischer et al, 2008), which may be one of the most critical signaling molecules (Fischer, 2011). Colchicine has also been determined to affect eye growth and development of myopia (Fischer et al, 1999b).…”

“…Fischer (2011) also focused on using chick retinas to demonstrate the regenerative potential of the retina. In damaged chick retinas, Müller glia, a cell type derived from neuroepithelial stem cells and distinct from the CMZ progenitor cells present in fish, amphibians, and birds, undergo de-differentiation to acquire progenitor phenotype, expressing Pax6, Chx10 (Fischer and Reh, 2001), Six3 (Fischer, 2005), Notch1 (Ghai et al, 2010; Hayes et al, 2007), and other factors found in retinal progenitor cells including Klf4 (Todd and Fischer, 2015) and asc11a (Fischer and Reh, 2001).…”

“…In damaged chick retinas, Müller glia, a cell type derived from neuroepithelial stem cells and distinct from the CMZ progenitor cells present in fish, amphibians, and birds, undergo de-differentiation to acquire progenitor phenotype, expressing Pax6, Chx10 (Fischer and Reh, 2001), Six3 (Fischer, 2005), Notch1 (Ghai et al, 2010; Hayes et al, 2007), and other factors found in retinal progenitor cells including Klf4 (Todd and Fischer, 2015) and asc11a (Fischer and Reh, 2001). Interestingly, these de-differentiated cell types are not found in the intact retina, possibly indicating that damage may induce signaling that causes Müller glia to revert (Fischer, 2011). Alternatively, given the finding that Müller glia-derived progenitor cells will go through multiple rounds of mitosis ex vivo compared to a single round of division in vivo (Fischer and Reh, 2001), Fischer (2011) posits that the intact retina suppresses Müller progenitor cells.…”

“…Interestingly, these de-differentiated cell types are not found in the intact retina, possibly indicating that damage may induce signaling that causes Müller glia to revert (Fischer, 2011). Alternatively, given the finding that Müller glia-derived progenitor cells will go through multiple rounds of mitosis ex vivo compared to a single round of division in vivo (Fischer and Reh, 2001), Fischer (2011) posits that the intact retina suppresses Müller progenitor cells. Although all Müller glia-derived progenitor cells have the ability to generate new neurons, only a small fraction of them do.…”

The ciliary marginal zone (CMZ) in development and regeneration of the vertebrate eye

“…Intraocular injections of glucagon inhibited the proliferation of CMZ progenitors, whereas a glucagon-receptor antagonist stimulated proliferation . Evidence suggests that glucagon released from the bullwhip and mini-bullwhip cells acts in opposition to insulin (or insulin-like growth factor) to regulate precisely the proliferation of retinal progenitors in the CMZ (Fischer, 2011;Fischer et al, 2005Fischer et al, , 2006.…”