Abstract
Neuronal degeneration in the zebrafish retina stimulates Müller glia (MG) to proliferate and generate multipotent progenitors for retinal repair. Controlling this proliferation is critical to successful regeneration. Previous studies reported that retinal injury stimulates pSmad3 signaling in injury-responsive MG. Contrary to these findings, we report pSmad3 expression is restricted to quiescent MG and suppressed in injury-responsive MG. Our data indicates that Tgfb3 is the ligand responsible for regulating pSmad3 expression. Remarkably, although overexpression of either Tgfb1b or Tgfb3 can stimulate pSmad3 expression in the injured retina, only Tgfb3 inhibits injury-dependent MG proliferation; suggesting the involvement of a non-canonical Tgfb signaling pathway. Furthermore, inhibition of Alk5, PP2A or Notch signaling rescues MG proliferation in Tgfb3 overexpressing zebrafish. Finally, we report that this Tgfb3 signaling pathway is active in zebrafish MG, but not those in mice, which may contribute to the different regenerative capabilities of MG from fish and mammals.
Highlights
Blinding eye diseases like macular degeneration, glaucoma, and diabetic retinopathy result in retinal neuron death which leads to vision loss
We found that phosphatase 2A (PP2A) or Notch inhibition partially rescued Muller glia (MG) proliferation in injured retinas overexpressing Tgfb3 and that Tgfb3 acts, at least in part, by stimulating Notch signaling
We found that Tgfb3-driven MG quiescence is associated with suppression of regeneration-associated genes
Summary
Blinding eye diseases like macular degeneration, glaucoma, and diabetic retinopathy result in retinal neuron death which leads to vision loss. Zebrafish have a remarkable ability to regenerate neurons that were lost due to injury or disease (Goldman, 2014; Lenkowski and Raymond, 2014; Wan and Goldman, 2016) Key to this regenerative response are Muller glia (MG) the major glial cell type in the retina of both fish and mammals. In fish, MG respond to retinal injury by dividing and generating multipotent progenitors for neuron regeneration (Bernardos et al, 2007; Fausett and Goldman, 2006; Fimbel et al, 2007; Powell et al, 2016; Ramachandran et al, 2010b; Raymond et al, 2006) It is not known why MG from fish and mammals respond differently to retinal injury, it likely results from differences in their environment and intrinsic differences that are reflected in their gene expression programs.
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