Proliferation Potential of Müller Glia after Retinal Damage Varies between Mouse Strains

Abstract

Retinal Müller glia can serve as a source for regeneration of damaged retinal neurons in fish, birds and mammals. However, the proliferation rate of Müller glia has been reported to be low in the mammalian retina. To overcome this problem, growth factors and morphogens have been studied as potent promoters of Müller glial proliferation, but the molecular mechanisms that limit the proliferation of Müller glia in the mammalian retina remain unknown. In the present study, we found that the degree of damage-induced Müller glia proliferation varies across mouse strains. In mouse line 129×1/SvJ (129), there was a significantly larger proliferative response compared with that observed in C57BL/6 (B6) after photoreceptor cell death. Treatment with a Glycogen synthase kinase 3 (GSK3) inhibitor enhanced the proliferation of Müller glia in 129 but not in B6 mouse retinas. We therefore focused on the different gene expression patterns during retinal degeneration between B6 and 129. Expression levels of Cyclin D1 and Nestin correlated with the degree of Müller glial proliferation. A comparison of genome-wide gene expression between B6 and 129 showed that distinct sets of genes were upregulated in the retinas after damage, including immune response genes and chromatin remodeling factors.

Wnt Regulates Proliferation and Neurogenic Potential of Müller Glial Cells via a Lin28/let-7 miRNA-Dependent Pathway in Adult Mammalian Retinas

“…In cultured mouse retinal explants, GSK3 inhibitor treatment enhances MG proliferation in SvJ129 mice (Suga et al, 2014). To investigate whether GSK3β deletion is sufficient to stimulate MG proliferation without retinal injury, we assayed EdU incorporation in the GSK3β loxp/loxp mouse retina infected with ShH10-GFAP-Cre at 4 weeks of age.…”

Age-dependent Müller glia neurogenic competence in the mouse retina

“…Since the total number of Calb1+BrdU+ cells was significantly lower in Gfap‐Cre::Rosa‐YFP retinas compared with our data with C57BL/6 mice (Figs. A and A1), we wondered if this might be due to the genetic mouse background (Suga et al, ). Thus, we generated the Gfap‐Cre::Rosa‐Ai9 mouse line, performed genetic lineage‐tracing with (not shown) and without adding BrdU, and observed more Calb1+Ai9+ cells compared with results with the Gfap‐Cre::Rosa‐YFP line (Fig.…”

Systemic 7,8-Dihydroxyflavone Treatment Protects Immature Retinas Against Hypoxic-Ischemic Injury via Müller Glia Regeneration and MAPK/ERK Activation

“…22 MG has also been shown to proliferate and produce neurons in several retinal injury models, albeit to a limited extent. 17 The regeneration of retinal neurons, such as bipolar or amacrine cells, by MG proliferation, can be enhanced by treatment with retinoid acid or growth factors in adult rodents. 23,24 We found significantly more BrdU þ cells in the retinas of HI-injured rats, indicating the high potential for cell proliferation after injury.…”

“…16 In rodents, MG can form new neurons, such as photoreceptors, but only in very limited numbers. 17 These responses are mediated by growth factors produced by retinal cells, such as the basic fibroblast growth factor and BDNF 10 and their enhancement can be an exciting strategy for retinal repair. 18 Here, we investigate whether DHF treatment can promote the proliferation and transdifferentiation of MG or other specific neuron subtypes and restore the function of the immature retina after HI injury.…”