Sox2-Deficient Müller Glia Disrupt the Structural and Functional Maturation of the Mammalian Retina

Abstract

PurposeMüller glia (MG), the principal glial cells of the vertebrate retina, display quiescent progenitor cell characteristics. They express key progenitor markers, including the high mobility group box transcription factor SOX2 and maintain a progenitor-like morphology. In the embryonic and mature central nervous system, SOX2 maintains neural stem cell identity. However, its function in committed Müller glia has yet to be determined.MethodsWe use inducible, MG-specific genetic ablation of Sox2 in vivo at the peak of MG genesis to analyze its function in the maturation of murine MG and effects on other cells in the retina. Histologic and functional analysis of the Sox2-deficient retinas is conducted at key points in postnatal development.ResultsAblation of Sox2 in the postnatal retina results in disorganization of MG processes in the inner plexiform layer and mislocalized cell bodies in the nuclear layers. This disorganization is concurrent with a thinning of the neural retina and disruption of neuronal processes in the inner and outer plexiform layers. Functional analysis by electroretinography reveals a decrease in the b-wave amplitude. Disruption of MG maturation due to Sox2 ablation therefore negatively affected the function of the retina.ConclusionsThese results demonstrate a novel role for SOX2 in glial process outgrowth and adhesion, and provide new insights into the essential role Müller glia play in the development of retinal cytoarchitecture. Prior to this work, SOX2 was known to have a primary role in determining cell fate. Our experiments bypass cell fate conversion to establish a new role for SOX2 in a committed cell lineage.

Sox2 regulates Müller glia reprogramming and proliferation in the regenerating zebrafish retina via Lin28 and Ascl1a

“…This is critical because it would reveal the function of the basal Sox2 expression in the Müller glia and amacrine cells and allow us to draw parallels to the conditional knockout phenotype observed in postnatal mouse Müller glia (Surzenko et al, 2013). Conditional knockout of sox2 in the adult zebrafish Müller glia could reveal if Sox2 is required for Müller glia maintenance, retinal cytoarchitecture, and retinal function as described in the postnatal mouse retina (Bachleda et al, 2016). Loss of Sox2 could alter these basal Müller glial functions, which may be required for Müller glia-derived neuronal regeneration through an unknown mechanism.…”

Sox2 conditional mutation in mouse causes ataxic symptoms, cerebellar vermis hypoplasia, and postnatal defects of Bergmann glia

“…In previously studied Sox2 mutant mouse models, the observed defects develop prenatally, or immediately after birth, and are related mainly to neural stem/progenitor cells defects. An exception is represented by abnormalities of GABAergic interneurons morphology and postmitotic migration (Cavallaro et al, ) in the forebrain, as well as defects of differentiated glia types: Mueller glia, a differentiated glial type of the eye, and oligodendroglia (Bachleda, Pevny, & Weiss, ; Hoffmann et al, ; Pevny & Nicolis, ).…”

Sox2 regulates astrocytic and vascular development in the retina

“…Recently, Sox2 was shown to be expressed, uniquely amongst retinal neurons, in the cholinergic amacrine cell population, where its conditional deletion affected the positioning of cholinergic somata and the stratification of their dendrites (Whitney et al, 2014). Sox2 has also been shown to be critical for developing Müller glia, as its conditional deletion from these cells alters their progenitor capacity and cellular morphology (Bachleda, Pevny, & Weiss, 2016; Surzenko, Crowl, Bachleda, Langer, & Pevny, 2013). The present study now highlights new roles for this transcription factor in retinal astrocytes, the only other cellular population expressing Sox2 in the mature retina.…”