Stimulating retinal neurogenesis from Müller glia

Abstract

Damage to the retina, through disease or injury, can lead to the permanent loss of neurons and ultimately loss of vision. Non-mammalian vertebrates have a robust ability to regenerate injured retinal neurons from Müller glial cells that activate the gene encoding the proneural factor Achaete-scute homolog 1 (Ascl1) and de-differentiate into progenitor cells. By contrast, mammalian Müller glia have a limited regenerative response and fail to upregulate Ascl1 after injury. In this work, I explored whether neurogenic transcription factors, including Ascl1, could restore neurogenic potential to mammalian Müller glia by overexpressing these factors in dissociated mouse Müller glial cultures and intact retinal explants. ASCL1-infected Müller glia upregulated retinal progenitor-specific genes and downregulated glial genes. Furthermore, ASCL1 remodeled the chromatin at its targets from a repressive to an active configuration. Müller glia-derived progenitors differentiated into cells that exhibited neuronal morphologies, expressed retinal subtype-specific neuronal markers and displayed neuron-like physiological responses. Additional neurogenic activators potentiated some of these effects. These results indicate that neural-promoting transcription factors can induce a neurogenic state in mature Müller glia, providing an alternative strategy for repair of the retina after disease or injury.