Comparison of Differential Activities of Three Basic Helix-Loop-Helix Transcription Factors in Stimulating Proliferation and Dedifferentiation of Müller Glia in Mouse Retina


Student thesis: Doctoral Thesis

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Award date16 Feb 2021


In a number of retinal degenerative diseases, vision impairment is caused by irreversible retinal neuron loss. Müller glia in mammals plays a quiescent role during retinal degeneration and goes through gliosis in response to injury, while they can be stimulated to regenerate neurons by supplementing additional growth factors and/or forced expression of certain transcription factors. The aim of this study is to regenerate retinal neurons by Müller glia, particularly focusing on comparison differential activities of three bHLH transcription factors in stimulating proliferation and dedifferentiation of Müller glia in mouse retina.

Three proneural basic helix-loop-helix (bHLH) transcription factors, Atoh7, ASCL1 and NeuroD1, direct neurogenesis at different stages and specify different cell types during retina development. To specifically study Müller glia that were stimulated by three bHLH transcription factors, I tested several methods of lineage tracing and confirmed that the transgenic mice Rosa26-Tdt; Glast-CreERt2 was specific and efficient to trace Müller glial cell fate in vivo. The results suggest that three bHLH transcription factors have different activities in stimulating Müller glia proliferation and dedifferentiation. ASCL1 was the most effective factors in stimulating Müller glia proliferation, while Atoh7 had the strongest effect on stimulation of Müller glia dedifferentiation. NeuroD1 did not have effect on stimulation of Müller glia regeneration in mouse retina.

This study suggests that three bHLH transcription factors reprogram Müller glia differently in proliferation or dedifferentiation, which are key processes of regeneration. Although the single factor could not further direct Müller glia-derived cells to retinal neurons, the study complements the understanding of stimulating Müller glia to enter the retinal regeneration program in mammalian retina by bHLH transcription factors.